TW200811169A - Chemical compounds - Google Patents

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TW200811169A
TW200811169A TW096117985A TW96117985A TW200811169A TW 200811169 A TW200811169 A TW 200811169A TW 096117985 A TW096117985 A TW 096117985A TW 96117985 A TW96117985 A TW 96117985A TW 200811169 A TW200811169 A TW 200811169A
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Taiwan
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amine
methyl
alkyl
propan
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TW096117985A
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Chinese (zh)
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Clifford Daivd Jones
Martin Pass
David Rudge
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Astrazeneca Ab
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Abstract

Compounds of formula (I), which possess cell-cycle inhibitory activity are described.

Description

200811169 九、發明說明： 【發明所屬之技術領域】 本發明係關於。密咬衍生物，礴1 A其樂學上可接受之鹽或活 體内可水解g旨’其具有細胞循環 衣抑制活性，且因此可用於 其抗細胞增生（譬如抗癌）活性 及因此可用於治療人類或 動物身體之方法中。本發明亦關认杂丨 Χ Θ办關於製造該嘧啶衍生物之方 法，含有彼等之醫藥組合物，及1 久具在樂劑製造上之用途， 其係在溫血動物譬如人類中，用 、 / 用於產生抗細胞增生作用。 【先前技術】 細胞循環係為細胞之存活、★ 一 ^ 肩即及增生之基礎，且係經 高度地調節，以確保各步驟以通 週矸且有秩序之方式進展。200811169 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to. a bite-derivative derivative, 礴1 A, which is a salt which is acceptable in culture or hydrolyzable in vivo, which has a cell cycle-coating inhibitory activity and is therefore useful for its anti-cell proliferative (e.g., anti-cancer) activity and thus useful for In the method of treating the human or animal body. The present invention also relates to a method for producing the pyrimidine derivative, a pharmaceutical composition containing the same, and a long-term use in the manufacture of a fungus, which is used in a warm-blooded animal such as a human. / Used to produce anti-cell proliferative effects. [Prior Art] The cell cycle is the basis for the survival of the cells, the shoulders and the proliferation, and is highly regulated to ensure that the steps progress in a thorough and orderly manner.

細胞經過細胞循環之推屎在、、店A 衣之進展係/原自於環素依賴性激酶(CDK) 族群數種成員之相繼活化盥去、、 ^ ，、云/舌化作用。CDK之活化作用 係依其與被稱為環素之胞内蛋白 皮曰貝麵群之交互作用而定。 環素會結合至CDK，且此締合作用係為細胞内之咖活性 所必須。不同環素係在細胞循環中之不同時點被表現與降 解’以確保CDK之活化鱼尖、、壬v 矢活以關於經過細胞循環進展之 正確順序發生。 再者，CDK顯示係為多種致离 裡双t基因發出訊息途徑之下游。 因素之向上调節及/或内源女 Α内源抑制劑之缺失所致之CDK活 性失5周’顯不係為在有辞分到 有、、糸刀衣原發出訊息途徑與腫瘤細胞 增生間之重要軸心。 因此’已明瞭的是，細胞循環激酶之抑制劑，特別是 CDK1、c題、CDK4及CDK6 (其係個別在隨、⑽舶細 120858 200811169 及G1 S期下插作）之抑制劑，應有價值地作為細胞增生（链 如哺乳動物癌細胞之生長)之活性抑制劑。 β 腫瘤細胞亦破認為係高度地依RNA聚合酉每Π之連續轉錄 而定’以保持適當含量之抗細胞〉周零蛋白冑，且確保 腫瘤細胞存活。特定言之，已知CDK1、CDK7、CDK8及CDK9 會經過蛋白暂夕r 士 ^ 、 末、功能部位之麟醯化作用，調節⑽a "" 之’舌丨生。因此，聚合酶II活性經過此等CDK抑 制d之抑制，可幫助腫瘤細胞中之前細胞凋零作用。 =期細胞循環激酶之抑制，在治療與逑行細胞循環及細 有關和之疾病狀態上是有價值的，譬如癌症（固態腫 ，與白血病）、纖維增生與分化病症、牛皮癖、風濕性關節 炎、卡波西氏肉瘤、血管瘤、急性與慢性腎病、動脈粥瘤、 動^粥瘤硬化、動脈再狹f、自身免疫疾病、急性與慢性 發炎、骨質疾病及伴隨著視網膜血管增生之眼部疾病。 WO 02/20512, WO 03/076435, WO 03/076436, WO 03/076434, WO 03/076433及WO 〇4/1〇1549係描述某些2_苯胺基冰味峻基嘴啶 衍生物，其會抑制細胞循環激酶之作用。本發明係基於發 現新穎組群之非苯胺基嘧啶會抑制CDK2之作用，且因此具 有抗細胞增生性質。 【發明内容】 因此，本發明係提供式①化合物： 120858 200811169The cells undergo a cell cycle, and the progression of the A, the A/A, and the members of the cyclin-dependent kinase (CDK) group are successively activated, ^, ^, and cloud/lingualization. The activation of CDK is based on its interaction with the intracellular protein mussel surface group known as cyclin. Cyclin binds to CDK and this association is required for intracellular coffee activity. Different cyclin lines are expressed and degraded at different points in the cell cycle to ensure that the activated fish tip, 壬v vector of CDK occurs in the correct order of progression through the cell cycle. Furthermore, the CDK display is downstream of a variety of signaling pathways for the di-t gene. The up-regulation of factors and/or the loss of CDK activity caused by the loss of endogenous inhibitors of endogenous privet endogenous inhibitors is not observed in the presence of a word, the path of the sputum, and the proliferation of tumor cells. The important axis between the two. Therefore, it has been clarified that inhibitors of cell cycle kinases, especially CDK1, c, CDK4 and CDK6 (which are inserted separately, and (10) are inserted under the 120858 200811169 and G1 S phase), should have Value as an inhibitor of the activity of cell proliferation (chains such as the growth of mammalian cancer cells). Beta tumor cells are also thought to be highly dependent on the continuous transcription of the RNA polymerase per ’ to maintain an appropriate level of anti-cell>peripherin and ensure tumor cell survival. In particular, CDK1, CDK7, CDK8, and CDK9 are known to regulate the (10)a "" Therefore, the inhibition of polymerase II activity by these CDK inhibitions can help the previous cell dysfunction in tumor cells. Inhibition of cell cycle kinases is valuable in the treatment of disease states related to cell cycle and fineness, such as cancer (solid swelling, and leukemia), fibroproliferation and differentiation disorders, psoriasis, rheumatoid joints Inflammation, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, atherosclerosis, arterial stenosis, autoimmune disease, acute and chronic inflammation, bone disease and eye with retinal vascular hyperplasia Ministry of disease. WO 02/20512, WO 03/076435, WO 03/076436, WO 03/076434, WO 03/076433, and WO 〇 4/1 〇 1549 describe certain 2-aniline-based ice-flavored pyridine derivatives, Will inhibit the role of cell cycle kinase. The present invention is based on the discovery that a novel group of non-anilinopyrimidines inhibits the action of CDK2 and thus has anti-cell proliferative properties. SUMMARY OF THE INVENTION Accordingly, the present invention provides a compound of formula 1: 120858 200811169

個氮原子與視情況選用 4S;其中環A之2個原子 可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Cl_6烷基、烷醯基、 胺甲醯基、N-(Ch烷基）胺甲醯基、N，NKCl _6烷基）胺甲醯基、 N-A·6烯基）胺曱醯基、N，N_(Cl·6烯基）胺甲醯基、胺石黃醯基、 N-((V6烧基）胺磺醯基、N，N_(Cl_6烷基h胺磺醯基、N·% &歸 基）胺磺醯基、Ν,Ν-Α-6烯基h胺磺醯基、Cu烷氧羰基、心 烧基〜醯基、C! - 6稀基確酿基、碳環基-R6或雜環基·发 中R1可視情況在碳上被一或多個R8取代；且其中若該雜譬 基含有-NH-部份基團，則該氮可視情況被選自R9之基團取 代； R2為奴上之取代基，且係選自鹵基、硝基、氰基、經基、 胺基、羧基、胺甲醯基、疏基、胺橫醯基、C1-6烧基、c2 烯基、Cm快基、Cm烷氧基、C^6烷醯基、Cb6烷醯氧基、 N_(Ch烷基）胺基、N’N-d6烷基h胺基、Cb6烷醯胺基、 iskCh烷基）胺甲醯基' ν,ν-cCh烷基h胺曱醯基、Cl-6烧基 120858 200811169 S(〇)a，其中a為〇至2，C〗a烷山健χτ/ 卜6况乳叛基、Ν-Α-6烷基）胺磺醯基、 N，N-(Cl.6燒基）2胺績醯基υ基績醯基胺基、碳環基 R或雜％基-11 ，其中R2可視情況在碳上被一或多個r12 取代；且其中若該雜環基含有视部份基團，則該氣可視 情況被選自R13之基團取代； q為04’ #中R2之意義可為相同或不同； R3係選自鹵基、氰基或胺基； 、it為0至2，其中R3之意義可為相同或不同； 、 R4係選自乙基、丙基、異丙基、丁基、異丁基、第二- 丁基、第二-丁基、環丙基、環丙基甲基、1-環丙基乙基、 環丁基甲基、環戊基或環丁基；其中R4可視情況在碳上被 一或多個R14取代； R5係選自甲基、乙基、異丙基、氟基甲基、二氟甲基、 三氟曱基、甲氧基甲基、環丙基甲基或環丙基； R6 與 R7 係獨立選自-C(〇)-、_c(〇)N(Ri5)_、_s(〇)2·或 -s〇2N(r16)_ ;其中圮5與1116係獨立選自氫或烷基； R8與R12係獨立選自鹵基、硝基、氰基、羥基、胺基、羧 基、胺曱醯基、巯基、胺磺醯基、c1-6烷基、c2-6烯基、c2 6 炔基、c卜6烷氧基、Cl-6烷醯基、Cl-6烷醯氧基、n_%_6烷 基）胺基、N，N-(Ch烷基）2胺基、（V6烷醯胺基、N-(CV6烷基） 胺曱醯基、Ν，Ν-(〇ν6烷基)2胺甲醯基、Cu烷基S(0)a，其中a 為0至2，（：卜6烷氧羰基、N-(Cl-6烷基）胺磺醯基、ν,Ν-Κη 烷基）2胺磺醯基、（^_6烷基磺醯基胺基、碳環基-R17-或雜環 基-R18 -，其中R8與R12可互相獨立地視情況在碳上被一或多 120858 200811169 個R19取代；且其中若該雜環基含有-勝部份基團，則該氮 可視情況被選自R2 0之基團取代； R，R及R係獨立選自燒基、燒酿基、Cu燒基 磺醯基、Ch燒氧魏基、胺甲醯基、n_(Ch燒基）胺甲醯基、 N’NKCh烧基）胺曱醯基、爷基、爷氧魏基、苯甲隨基及苯 基磺醯基，其中R9，Ri3&R2〇可互相獨立地視情況在碳上被 一或多個R2 1取代；The nitrogen atom is optionally selected from 4S; wherein two atoms of ring A may be linked by a bridging group; R1 is a substituent on nitrogen and is selected from the group consisting of hydrogen, Cl_6 alkyl, alkane fluorenyl, amine carbaryl, N-(Ch alkyl)aminecarbamyl, N,NKCl -6 alkyl)aminocarbazinyl, NA.6 alkenyl)amine fluorenyl, N,N-(Cl.6 alkenyl)amine methyl sulfhydryl, Amine sulphate, N-((V6 alkyl)amine sulfonyl, N,N_(Cl_6 alkylhethanesulfonyl, N·% & sulfhydryl)amine sulfonyl, hydrazine, fluorene-fluorene-6 Alkenylh-amine sulfonyl group, Cu alkoxycarbonyl group, cardioalkyl-fluorenyl group, C!-6-based aryl group, carbocyclyl-R6 or heterocyclic group, R1 may be one on carbon Or a plurality of R8 substitutions; and wherein if the heterofluorenyl group contains a -NH- moiety, the nitrogen may optionally be substituted with a group selected from R9; R2 is a substituent substituent and is selected from a halo group , nitro, cyano, thiol, amine, carboxyl, amine carbaryl, sulfhydryl, amine fluorenyl, C1-6 alkyl, c2 alkenyl, Cm fast radical, Cm alkoxy, C^6 Alkenyl, Cb6 alkoxy, N_(Ch alkyl)amine, N'N-d6 alkylh-amino, Cb6 alkanoyl, iskCh alkyl)amine Methyl ketone ' ν, ν-cCh alkyl h amine fluorenyl, Cl-6 alkyl 120858 200811169 S (〇) a, where a is 〇 to 2, C 〗 〖Azanshan χ τ / 卜6 condition milk rebel , Ν-Α-6 alkyl)amine sulfonyl, N,N-(Cl.6 alkyl) 2 amine fluorenyl hydrazino, carbocyclyl R or hetero yl-11, wherein R2 may optionally be substituted on the carbon by one or more r12; and wherein if the heterocyclic group contains a moiety, the gas may be optionally substituted with a group selected from R13; q is 04'#R2 The meaning may be the same or different; R3 is selected from a halogen group, a cyano group or an amine group; and it is 0 to 2, wherein the meaning of R3 may be the same or different; and R4 is selected from the group consisting of ethyl, propyl and isopropyl. Base, butyl, isobutyl, second-butyl, second-butyl, cyclopropyl, cyclopropylmethyl, 1-cyclopropylethyl, cyclobutylmethyl, cyclopentyl or cyclobutyl Wherein R4 may optionally be substituted on the carbon by one or more R14; R5 is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl , cyclopropylmethyl or cyclopropyl; R6 and R7 are independently selected from -C(〇)-, _c(〇)N(Ri5)_ _s(〇)2· or -s〇2N(r16)_; wherein 圮5 and 1116 are independently selected from hydrogen or alkyl; R8 and R12 are independently selected from halo, nitro, cyano, hydroxy, amine , carboxyl, amine fluorenyl, fluorenyl, sulfonyl, c1-6 alkyl, c2-6 alkenyl, c2 6 alkynyl, c a 6 alkoxy, Cl-6 alkanoyl, Cl-6 alkane Alkoxy, n_%_6 alkyl)amino, N,N-(Ch alkyl) 2 amine, (V6 alkanoamine, N-(CV6 alkyl) aminyl, hydrazine, hydrazine-( 〇ν6 alkyl)2-aminomethylindenyl, Cu alkyl S(0)a, wherein a is 0 to 2, (: 6 alkoxycarbonyl, N-(Cl-6 alkyl)amine sulfonyl, ν , Ν-Κη alkyl) 2 amine sulfonyl, (^_6 alkylsulfonylamino, carbocyclyl-R17- or heterocyclyl-R18-, wherein R8 and R12 may independently of each other in the case of carbon Substituted by one or more 120858 200811169 R19; and wherein if the heterocyclic group contains a - moiety, the nitrogen may optionally be substituted with a group selected from R 2 0; R, R and R are independently selected from Burning base, calcined base, Cu-based sulfonyl group, Ch-Oxygen-based group, amine-mercapto group, n-(Ch-alkyl)-aminomethyl group, N'NKCh-based amine sulfhydryl group, aryl group, Oxyweiwei And a benzyl group and a phenylsulfonyl group, wherein R9, Ri3&R2, independently of each other, may be substituted on the carbon by one or more R2 1 ;

R10，RU，R17及Ris係獨立選自直接鍵結…〇_、_N(R22)_、 -C(O)-、-N(R23)C(0)-、-C(0)N(R24)-、-s(0)s-、-S02N(R25)·或 -N(R26)S〇2_ ;其中R22, R23, R24, R25及R26係獨立選自氫或 Ci-6烷基，且s為0-2 ; R14係選自鹵基、硝基、氰基、羥基、胺基、羧基、胺甲 醯基、毓基、胺磺醯基、（^_6烷氧基、Q-6烷醯基、（^_6烷 醯氧基、N-(Ch烷基）胺基、N，N-(Ch烷基）2胺基、（：卜6烷醯 胺基、NJCh烷基）胺曱醯基、N，N-(Ch烷基）2胺曱醯基、（：卜6 烷基S(0)a，其中a為0至2，CV6烷氧羰基、Ν-(〇ν6烷基）胺磺 醯基、N^Ch烷基）2胺磺醯基及烷基磺醯基胺基；且 R19與R21係獨立選自鹵基、硝基、氰基、羥基、三氟甲 氧基、三氟曱基、胺基、魏基、胺曱醯基、疏基、胺石黃酸 基、甲基、乙基、丙基、異丙基、環丙基、環丁基、甲氧 基、乙氧基、乙醯基、乙醯氧基 '甲胺基、乙胺基、二甲 胺基、二乙胺基、N-甲基-N-乙胺基、乙醯胺基、N-甲基胺 甲醯基、N-乙基胺曱醯基、N，N-二甲基胺甲醯基、n，N-二乙 基胺甲酿基、N-甲基-N-乙基胺甲酿基、甲硫基、乙硫基、 120858 -10- 200811169 甲基亞基、乙基亞磺醯基、甲烷磺醯基、乙基磺醯基、 甲氧叛基、乙氧幾基、Ν_甲基胺4醯基、①乙基胺續醯基、 Ν，Ν-二甲基胺伽基、Ν，Ν•二乙基料醯基或㈣基·队乙基 胺磺醢基； 1 或其藥學上可接受之鹽或活體内可水解酯。 根據本發明之進一步特徵，係提供式①化合物 描緣），其中： ^ 環A為5-7員飽和雜環，其含有一個氮原子與視情況選用 之1或2個其他雜原子，選自N、〇或3;其中環A之2個原子 可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Ci·6烷基、。^烷醯基、 胺甲醯基、N-%·6烷基）胺甲醯基、N，N_(Ci·6烷基）胺甲醯基、 N-d6烯基）胺甲醯基、N，N_(Ci·6烯基）胺甲醯基、胺磺醯基、 泳说-6烷基）胺磺醯基、N,N_(Ci_6烷基h胺磺醯基、ν_%·6烯 基）胺磺醯基、Ν，Ν-((νό烯基h胺磺醯基、Cl_6烷氧羰基、Ci_6 烧基磺醯基、Q—6烯基磺醯基、碳環基-R6或雜環基—R7 ;其 中R1可視情況在碳上被一或多個R8取代；且其中若該雜環 基含有-NH-部份基團，則該氮可視情況被選自R9之基團取 代； R2為碳上之取代基，且係選自鹵基、硝基、氰基、經基、 胺基、敗基、胺甲醯基、魏基、胺續醯基、q _ 6烧基、c2 6 烯基、C：2·6炔基、Cm烷氧基、烷醯基、C1-6烷醯氧基、 N-(Ch烷基）胺基、N，N_(C卜6烷基）2胺基、烷醯胺基、 N·%-6烷基）胺甲醯基、烷基h胺曱醯基、Cl-6烷基 120858 11 200811169 S(0)a，其中a為0至2，Ch烷氧羰基、N_(Ci 6烷基）胺磺醯基、 Ν,Ν-Α-6烷基h胺磺醯基、Ci_6烷基磺醯基胺基、碳環基 -R10-或雜環基-R11-;其中R2可視情況在碳上被一或多個rU 取代，且其中若該雜環基含有__-部份基團，則該氮可視 情況被選自R13之基團取代； q為0-4 ;其中R2之意義可為相同或不同； R3係選自鹵基、氰基或胺基； η為0至2 ’其中R3之意義可為相同或不同； R4係選自乙基、丙基、異丙基、丁基、異丁基、第二· 丁基、弟二-丁基、環丙基、環丙基甲基、卜環丙基乙基、 環丁基甲基、環戊基或環丁基；其中R4可視情況在碳上被 一或多個R14取代； R5係選自甲基、乙基、異丙基、氟基甲基、二氟甲基、 三氟曱基、甲氧基甲基、環丙基曱基或環丙基； R6 與 R7 係獨立選自 _C(〇)_、_c(0)N(R15)-、-S(0)2-或 -s〇2N(r16)·;其中ris與ru係獨立選自氫或c^6烷基； R8與R12係獨立選自鹵基、硝基、氰基、羥基、胺基、羧 基、胺甲醯基、巯基、胺磺醯基、Cl-6烷基、C26烯基、c2-6 炔基、Ch烷氧基、q_6烷醯基、C卜6烷醯氧基、N-(C卜6烷 基）胺基、HN-Cu烷基）2胺基、Ch烷醯胺基、NKCu烷基） 胺曱醯基、N^Ch烷基)2胺甲醯基、Cu烷基S(0)a，其中a 為0至2，Ch烷氧羰基、N-(Ch烷基）胺磺醯基、 烧基)2胺續醯基、Cl - 6烧基績醯基胺基、碳環基-R1 7 -或雜環 基-R18-;其中R8與R12可互相獨立地視情況在碳上被一或多 120858 •12- 200811169 部份基團，則該氮 似19取代；且其中若該雜環基… 可視情況被選自R2〇之基團取代； R9，R13及R2»係獨立選自Γ ^ ^ η ^ 、目h烧基、Cl 6烷酿基、&烧基 績酿基、胺甲醯基、哪卜6燒基)胺曱醯基、 N，N-(Cl-6烧基）胺甲醯基、爷基、爷氧幾基、苯甲酿基及笨 基續醯基；其中R'mR2。可互相獨立地視情況在碳上被 一或多個R2 1取代；R10, RU, R17 and Ris are independently selected from direct bonding...〇_, _N(R22)_, -C(O)-, -N(R23)C(0)-, -C(0)N(R24 )-, -s(0)s-, -S02N(R25)· or -N(R26)S〇2_; wherein R22, R23, R24, R25 and R26 are independently selected from hydrogen or Ci-6 alkyl, and s is 0-2; R14 is selected from the group consisting of halo, nitro, cyano, hydroxy, amine, carboxy, aminemethanyl, fluorenyl, sulfonyl, (^-6 alkoxy, Q-6 alkane) Indenyl, (^_6 alkyl alkoxy, N-(Ch alkyl)amino, N,N-(Ch alkyl) 2 amine, (: 6 alkyl alkanoyl, NJCh alkyl) amine hydrazine , N,N-(Ch alkyl) 2 amine fluorenyl, (: 6 alkyl S(0)a, wherein a is 0 to 2, CV6 alkoxycarbonyl, Ν-(〇ν6 alkyl)amine Sulfosyl, N^Ch alkyl) 2 amine sulfonyl and alkyl sulfonylamino; and R19 and R21 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, tri Fluorinyl, amine, weiki, amine sulfhydryl, sulfhydryl, urushi, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, B Oxyl, ethoxylated, ethoxylated 'methylamino, ethylamino, dimethylamino, diethylamine , N-methyl-N-ethylamino, acetamido, N-methylamine, fluorenyl, N-ethylamine decyl, N,N-dimethylamine, fluorenyl, n, N -diethylamine methyl, N-methyl-N-ethylamine methyl, methylthio, ethylthio, 120858 -10- 200811169 methyl subunit, ethyl sulfinyl, methane sulfonate Sulfhydryl, ethylsulfonyl, methoxyhistyl, ethoxyxo, Ν-methylamine 4 fluorenyl, 1 ethylamine fluorenyl, hydrazine, hydrazine-dimethylamine gamma, hydrazine, hydrazine • diethyl sulfhydryl or (tetra) benzyl ethyl sulfonamide; 1 or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. According to a further feature of the invention, a compound of formula 1 is provided) , wherein: ^ Ring A is a 5-7 membered saturated heterocyclic ring containing a nitrogen atom and optionally 1 or 2 other heteroatoms selected from N, hydrazine or 3; wherein 2 of the ring A may be considered as appropriate Attached to the bridging group; R1 is a substituent on the nitrogen, and is selected from the group consisting of hydrogen, Ci.6 alkyl, alkyl alkanoyl, amine carbaryl, N-.6 alkyl)amine carbhydryl, N , N_(Ci.6 alkyl)amine,carboxylidene, N-d6 alkenyl)amine,carboxylidene, N,N((Ci.6 alkenyl)amine Mercapto, sulfonyl, -6 alkyl) sulfonyl, N,N_(Ci_6 alkylhhoxasulfonyl, ν_%·6 alkenyl)amine sulfonyl, hydrazine, hydrazine- ((νό alkenylhethanesulfonyl, Cl_6 alkoxycarbonyl, Ci_6 alkylsulfonyl, Q-6 alkenylsulfonyl, carbocyclyl-R6 or heterocyclyl-R7; wherein R1 may be in the carbon Substituted by one or more R8; and wherein if the heterocyclic group contains a -NH- moiety, the nitrogen may optionally be substituted with a group selected from R9; R2 is a substituent on carbon and is selected From halo, nitro, cyano, meridin, amine, acetonyl, carbyl, fluorenyl, fluorenyl, alkyl hydrazino, q -6 alkyl, c 2 6 alkenyl, C: 2 · alkynyl , Cm alkoxy, alkanoyl, C1-6 alkoxy, N-(Ch alkyl)amine, N,N_(C 6 alkyl) 2 amine, alkanoamine, N·% -6 alkyl)amine mercapto, alkyl h-amine sulfhydryl, Cl-6 alkyl 120858 11 200811169 S(0)a, wherein a is 0 to 2, Ch alkoxycarbonyl, N_(Ci 6 alkyl Aminesulfonyl, anthracene, fluorenyl-fluorenyl-6-alkylh-sulfonyl, Ci_6 alkylsulfonylamino, carbocyclyl-R10- or heterocyclyl-R11-; wherein R2 may be in the carbon One or more rU is substituted, and wherein if the heterocyclic group contains a _-- moiety, the nitrogen may be optionally substituted with a group selected from R13; q is 0-4; wherein the meaning of R2 may be the same or different; R3 Is selected from a halogen group, a cyano group or an amine group; η is 0 to 2 ' wherein R3 may be the same or different; R4 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, and Dibutyl, di-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl or cyclobutyl; wherein R4 may be taken on carbon by one or a plurality of R14 substituted; R5 is selected from the group consisting of methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxymethyl, cyclopropylindenyl or cyclopropyl; R6 and R7 are independently selected from _C(〇)_, _c(0)N(R15)-, -S(0)2- or -s〇2N(r16)·; wherein ris and ru are independently selected from hydrogen Or c^6 alkyl; R8 and R12 are independently selected from the group consisting of halo, nitro, cyano, hydroxy, amine, carboxy, carbamoyl, fluorenyl, sulfonyl, Cl-6, C26 Base, c2-6 alkynyl group, Ch alkoxy group, q_6 alkyl fluorenyl group, C 6 6 alkyl decyloxy group, N-(C s 6 alkyl) amine group HN-Cu alkyl) 2 amine group, Ch alkanoguanidino group, NKCu alkyl group) Amidino group, N^Ch alkyl group 2 amine methyl group, Cu alkyl S(0)a, wherein a is 0 To 2,Ch alkoxycarbonyl, N-(Ch alkyl)amine sulfonyl, decyl 2 amine fluorenyl, Cl 6 alkyl fluorenyl, carbocyclyl-R1 7 - or heterocyclic a group -R18-; wherein R8 and R12 are independently of each other on the carbon by one or more of 120858 • 12- 200811169 part of the group, then the nitrogen is like 19; and wherein if the heterocyclic group... Substituted from R2〇; R9, R13 and R2» are independently selected from Γ ^ ^ η ^ , 目 h alkyl, Cl 6 alkyl, & calcined base, amine methyl sulfhydryl, which a 6-alkyl group, an amine group, an N,N-(Cl-6 alkyl)amine, a fluorenyl group, a fluorenyl group, a benzoyl group, and a phenyl group; wherein R'mR2. Can be independently substituted on the carbon by one or more R 2 1 ;

R10, R11，R17及R18係獨立選自直接鍵結、_〇·、_n(r22)_、 -C(0). . -N(R^)C(〇)- . -0(0)^^4). . _S(〇)s. . .s〇2N(R-)-^ -N(R26)S02-，其中R22，R23，r2 4，妒5及R26係獨立選自氫或 C卜6烷基，且S為0-2 ; R14係選自鹵基、硝基、氰基、羥基、胺基、羧基、胺曱 酸基、巯基、胺磺醯基、（^_6烷氧基、（^_6烷醯基、（V6烷 醯氧基、N-CCh烷基）胺基、Ν,Ν-Κη烷基）2胺基、c卜6烷醯 胺基、N-(Ch烷基）胺曱醯基、N，N-((V6烷基）2胺甲醯基、Ch 烷基S(0)a，其中a為0至2，（V6烷氧羰基、N_((V6烷基）胺磺 醯基、N，N-(Cu院基）2胺確醯基及q _ 6烧基橫醯基胺基；且 R19與r2i係獨立選自鹵基、硝基、氰基、羥基、三氟甲 氧基、三氟甲基、胺基、羧基、胺甲醯基、巯基、胺磺醯 基、甲基、乙基、環丙基、環丁基、甲氧基、乙氧基、乙 醯基、乙醯氧基、甲胺基、乙胺基、二甲胺基、二乙胺基、 N-甲基乙胺基、乙醯胺基、Ν·甲基胺甲醯基、N-乙基胺 甲醯基、Ν，Ν-二甲基胺甲醯基、Ν，Ν-二乙基胺甲醯基、甲 基乙基胺甲酿基、甲硫基、乙硫基、甲基亞石黃醯基、乙 120858 -13 - 200811169 基亞磺醯基、甲烷磺醯基、乙基磺醯基、甲氧羰基、乙氧 羰基、N-甲基胺磺醯基、N-乙基胺磺醯基、N，N-二甲基胺磺 醯基、N，N-二乙基胺磺醯基或N-甲基_N_乙基胺磺醯基； 或其藥學上可接受之鹽或活體内可水解g旨。R10, R11, R17 and R18 are independently selected from direct bond, _〇·, _n(r22)_, -C(0). . -N(R^)C(〇)- . -0(0)^ ^4). . _S(〇)s. . .s〇2N(R-)-^ -N(R26)S02-, wherein R22, R23, r2 4, 妒5 and R26 are independently selected from hydrogen or C 6 alkyl, and S is 0-2; R14 is selected from the group consisting of a halogen group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an amine decanoic acid group, a fluorenyl group, an amine sulfonyl group, (^_6 alkoxy group, (^_6 alkyl fluorenyl, (V6 alkyl decyloxy, N-CCh alkyl) amine group, hydrazine, Ν-Κη alkyl) 2 amine group, c -6 alkyl amidino group, N-(Ch alkyl group) Amidino, N,N-((V6 alkyl)2 aminecarboxamidine, Ch alkyl S(0)a, wherein a is 0 to 2, (V6 alkoxycarbonyl, N_((V6 alkyl)) Aminesulfonyl, N,N-(Cu-based) 2 amine thiol and q -6 alkyl-based fluorenylamino; and R19 and r2i are independently selected from halo, nitro, cyano, hydroxy, Trifluoromethoxy, trifluoromethyl, amine, carboxyl, amine indenyl, fluorenyl, sulfonyl, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, Ethylene, ethoxylated, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl Base, acetamino group, Ν·methylamine carbhydryl group, N-ethylamine methyl sulfhydryl, hydrazine, hydrazine-dimethylamine carbhydryl, hydrazine, hydrazine-diethylamine carbhydryl, A Ethyl ethylamine, methylthio, ethylthio, methyl sulphate, ethyl 120858 -13 - 200811169 sulfinyl, methanesulfonyl, ethylsulfonyl, methoxycarbonyl, B Oxycarbonyl, N-methylamine sulfonyl, N-ethylamine sulfonyl, N,N-dimethylamine sulfonyl, N,N-diethylamine sulfonyl or N-methyl _ N-ethylamine sulfonyl; or a pharmaceutically acceptable salt thereof or hydrolyzable in vivo.

在本專利說明書中，”烷基” 一詞係包括直鏈與分枝鏈烷 基兩者，但對個別烷基譬如，，丙基”之指稱，係僅專指直鏈 k型。例如，"C^烷基”係包括甲基、乙基、丙基、異丙基 及第三-丁基。但是，對個別烷基譬如”丙基”之指稱，係僅 專指直鏈變型，而對個別分枝鏈烷基譬如，，異丙基，，之指稱， 係僅專指分枝鏈變型。類似慣例係適用於其他基團。"齒基" 一詞係指氟基、氯基、溴基及碘基。 f選用取代基係選自，，一或多個，，基團之情況中，應明瞭 的是此定義係包括所有取代基均選自所指定基團之一，或 取代基係選自所指定基團中之兩種或多種。 環A為"5_7員飽和雜環，其含有一個氮原子與視情況選用 乂或2個其他雜原子’選自N、〇或8”。，，5_7員飽和雜環， 其含有—個氮原子與視情況選用之_個其他雜原子，選 自N、〇或s" ’係為飽和雜環，其含有& 6或7個原子，其 中至少一個為氮原子（Rl所連接），而其他為碳 個選自^、〇或8之其他 于及1或2 ⑽㈣ ，、㈣原子，其中偶·基團可視情況被 換。5-7員飽和雜環，其含有一個氮原子與視 選用之1或2個其他雜原子 月， > tr 41 4 b之特定實例為 “炖…基、六氫吡畊+基、3-酮基六氫吡啶i^ 基。 疋+基及四氫 120858 •14- 200811169 一 ％A之兩個原子可視情況被橋基連接。橋基為一個鍵結， 、個原子或兩個原+，連接環八之兩個不同原子。在橋基 ^或兩個原子之情況下，該原子可獨立選自碳、氮、硫 或氧。㈣言 <，橋基為直接鍵結。特定言之，橋基為一 個碳原子。或#，橋基為兩個碳原子。或者，橋基為一個 &原子與-個氮原子。”5_7員飽和雜環’其含有—個氮原子 與視情況選用之丨或2個其他雜原子，選自N、〇或s，其中 環A之2個原子”係”被橋基連接；，，之實例，係包括孓氮雙 壞开[3.2.1]辛冰基、6,8-二氮雙環并拉狀I基、3-氮雙環并 [3·1·0]己-6_基、2-氮雙環并[2丄〇]戊-5-基、8-氮雙環并[3·2·1]辛_3_ 基或内向各氮雙環并[3.2.1]辛各基。 π雜環基”為飽和、部份飽和或不飽和，單或雙環狀環， 含有4-12個原子，其中至少一個原子係選自氮、硫或氧， 除非另有指明，否則其可經碳或氮連接，其中-CH2-基團可 視情況被-c(o)-置換，環氮原子可視情況帶有Ci 6烷基，且 形成四級化合物，或環氮及/或硫原子可視情況被氧化，以 形成N-氧化物與或S-氧化物。”雜環基”一詞之實例與適當 意義為嗎福啉基、六氫吡啶基、吡啶基、哌喃基、吨ρ各基、 異嘧唑基' W哚基、喳啉基、嘍吩基、丨^苯并二氧伍圜晞 基、遠二唑基、六氫吡畊基、嘍唑啶基、四氫吡η各基、硫 代嗎福啉基、二氫吡咯基、高六氫吡畊基、3,5_二氧六氫峨 π定基 '四氫派喃基、咪嗤基、哺咬基、ρ比啡基、塔喷基、 異崎唑基、Ν-曱基吡洛基、4-吡咬酮、μ異峻淋酮、2-四氮 吡咯酮、4-嘧唑啶酮、吡啶-Ν-氧化物及喹啉_Ν_氧化物。於 120858 -15- 200811169 本發"明之_ -Γ- ’雜環基π為飽和、部份飽和或不飽和， 單或又衣狀％，含有5或6個原子，其中至少一個原子係選 自氮、硫或氧，除非另有指明，否則其可經碳或氮連結， 2 土團了視^況被_C(〇)_置換，而環硫原子可視情況被 氧化，以形成S-氧化物。為避免疑惑，"雜環基，，亦包括上 文疋義之經橋接化合物，例如7-氮雙環并[2.2.1]庚烷與6-氮雙 晨并[2.2.2]辛燒。’碳環基,,為飽和、部份飽和或不飽和，單 或雙環狀碳環，含有3-12個原子；其中-CH2-基團可視情況 被-C(O)-置換。特定言之，，，碳環基，，為含有5或6個原子之 單壤狀環’或含有9或1〇個原子之雙環狀環。關於，，碳環基” 之適當意義包括環丙基、環丁基、μ酮基環戊基、環戊基、 環戊稀基、環己基、環己烯基、苯基、莕基、四氫莕基、 氫茚基或1-酮基氫茚基。 nC^6燒氧羰基”之實例包括甲氧羰基、乙氧羰基、正-與 第三-丁氧羰基。”C!-6烷氧基”之實例包括曱氧基、乙氧基 及丙氧基。’’C^烷基s(0)a，其中a為0至2”之實例包括曱硫 基、乙硫基、甲基亞磺醯基、乙基亞磺醯基、甲烷磺醯基 及乙基石頁酿基。’’C! _6烧酿基”之實例包括丙酿基與乙酿基。 nCi-6烷醯氧基”之實例包括丙醯氧基與乙醯氧基。"Ci-6烷 醯胺基’’之實例包括丙醯基胺基與乙醯胺基。”C2-6烯基”之 實例包括乙烯基、烯丙基及1-丙烯基。”c2_6炔基”之實例包 括乙炔基、1-丙炔基及2-丙炔基。’’N-Cu烷基）胺磺醯基’’之 實例包括N-(甲基）胺磺醯基與N-(乙基）胺磺醯基。"Ν，Ν-((^ _6 烷基）2胺磺醯基”之實例包括Ν，Ν-(二甲基）胺磺醯基與Ν_(曱 120858 -16- 200811169 基）-N-(乙基）胺磺醯基。"Ν-(ίν6烯基）胺磺醯基”之實例包括 Ν-(烯丙基）胺磺醯基與Ν-(乙烯基）胺磺醯基。"Ν,Ν-Θ! -6烯基）2 胺磺醯基，，之實例包括Ν，Ν-(二烯丙基）胺磺醯基與Ν-(烯丙 基）-Ν-(乙烯基）胺磺醯基。”N-(Ch烷基）胺甲醯基，，之實例包 括甲胺基羰基與乙胺基羰基。，’Ν，Ν-((^_6烷基）2胺甲醯基”之 實例包括二甲胺基羰基與甲基乙胺基羰基。•’N-CC! -6烯基） 胺甲醯基’’之實例包括烯丙基胺基羰基與乙烯基胺基羰基。 ”Ν,Ν·% _6烯基）2胺曱醯基”之實例包括二烯丙基胺基羰基 與（稀丙基）(乙烯基）胺基羰基。” C! -6烷基磺醯基，，之實例包 括甲基磺醯基與異丙基磺醯基。”Cii烯基磺醯基，，之實例包 括烯丙基績醯基與乙烯基績醯基。_ 6烧基績醯基胺基” 之實例包括甲烧績酸基胺基與異丙基續醯基胺基。” Ν·% _ 6 烧基）胺基’’之實例包括曱胺基與乙胺基。”N，N-(Ci 烷基）2 胺基"之實例包括二-N-甲胺基、二_(N_乙基）胺基及N_乙基_N_ 甲胺基。 本發明化合物之適當藥學上可接受之鹽，為例如足夠鹼 性之本發明化合物之酸加成鹽，例如與無機或有機酸之酸 加成鹽，該酸例如鹽酸' 氫溴酸、硫酸、磷酸、三 足夠酸性之本發明化合物之 鹽，例如鈉或鉀鹽，鹼土金In the present specification, the term "alkyl" is used to include both straight-chain and branched-chain alkyl groups, but for individual alkyl groups, for example, propyl" refers to only the linear k-type. For example, "C^alkyl" includes methyl, ethyl, propyl, isopropyl and tert-butyl. However, references to individual alkyl hydrazines such as "propyl" are exclusively meant to be straight-chain variants, whereas for individual branched-chain alkyl radicals, such as isopropyl, the reference refers exclusively to branched chain variants. Similar conventions apply to other groups. The term "dental base" refers to fluoro, chloro, bromo and iodo. Wherein the substituent is selected from the group consisting of one or more, in the case of a group, it should be understood that the definition includes all substituents selected from one of the specified groups, or the substituents are selected from the specified Two or more of the groups. Ring A is a "5_7 member saturated heterocyclic ring containing a nitrogen atom and optionally 乂 or 2 other heteroatoms selected from N, 〇 or 8", a 5-7-membered saturated heterocyclic ring containing a nitrogen The atom and optionally the other hetero atom selected from N, 〇 or s" ' is a saturated heterocyclic ring containing & 6 or 7 atoms, at least one of which is a nitrogen atom (connected by Rl), and Others are carbon selected from the group consisting of ^, 〇 or 8 and 1 or 2 (10) (4), (4) atoms, wherein the even group may be exchanged. 5-7 member saturated heterocyclic ring, which contains a nitrogen atom and A specific example of 1 or 2 other heteroatoms, > tr 41 4 b is "boiled base, hexahydropyridinium + base, 3-ketohexahydropyridine".疋+ base and tetrahydro 120858 •14- 200811169 One of the two atoms of %A can be connected by a bridge base depending on the situation. The bridging group is a bond, an atom or two original +, connecting two different atoms of the ring eight. In the case of a bridging group or two atoms, the atom may be independently selected from carbon, nitrogen, sulfur or oxygen. (4) Words <, the bridging group is a direct bond. In particular, the bridging group is a carbon atom. Or #, the bridging group is two carbon atoms. Alternatively, the bridging group is an & atom and a nitrogen atom. "5_7 member saturated heterocyclic ring" which contains - a nitrogen atom and optionally hydrazine or two other heteroatoms selected from N, hydrazine or s, wherein the two atoms of ring A are "bridged" by a bridging group; Examples include 孓 双 坏 坏 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ -Nubybicyclo[2丄〇]pent-5-yl, 8-azabicyclo[3·2·1]octyl-3-yl or inward-directed nitrogen bicyclo[3.2.1]octyl. πheterocyclyl "Saturated, partially saturated or unsaturated, mono- or bicyclic ring containing 4-12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen. Unless otherwise indicated, it may be carbon or nitrogen. a linkage wherein the -CH2- group may be optionally replaced by -c(o)-, the ring nitrogen atom optionally bearing a Ci 6 alkyl group, and forming a quaternary compound, or the ring nitrogen and/or sulfur atom may be oxidized as appropriate, To form an N-oxide and or an S-oxide. Examples and meanings of the term "heterocyclyl" are morpholinyl, hexahydropyridyl, pyridyl, piperidyl, tonnol, isopyrazolyl 'W decyl, porphyrin, porphin Benzo, benzodioxanthene, faradiazolyl, hexahydropyrrole, oxazolidinyl, tetrahydropyridinyl, thiomorpholinyl, dihydropyrrolyl, high six Hydropyridyl, 3,5-dihydrohexahydroindole π-decyl 'tetrahydropyranyl, imidinyl, carbyl, ρ morphinyl, phenylpyrazine, isosazolyl, Ν-mercaptopyridyl Loki, 4-pyridone, mupirone, 2-tetrazolopyrone, 4-pyrazolidinone, pyridine-rhodium-oxide and quinoline-Ν-oxide.于120858 -15- 200811169 本发"明之_ -Γ- 'Heterocyclyl π is saturated, partially saturated or unsaturated, single or smear-like, containing 5 or 6 atoms, at least one of which is selected From nitrogen, sulfur or oxygen, unless otherwise specified, it may be linked by carbon or nitrogen, 2 earth is replaced by _C(〇)_, and the ring sulfur atom may be oxidized as appropriate to form S- Oxide. For the avoidance of doubt, "heterocyclyl, also includes the above-mentioned bridged compounds, such as 7-azabicyclo[2.2.1]heptane and 6-nitrobis-[2.2.2] octane. The carbocyclic group, which is saturated, partially saturated or unsaturated, has a mono or bicyclic carbocyclic ring containing from 3 to 12 atoms; wherein the -CH2- group may be optionally substituted by -C(O)-. Specifically, a carbocyclic group is a single-ring ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 1 atom. Suitable meanings for "carbocyclyl" include cyclopropyl, cyclobutyl, μketocyclopentyl, cyclopentyl, cyclopentyl, cyclohexyl, cyclohexenyl, phenyl, decyl, tetra Examples of the hydroquinone group, the hydroquinone group or the 1-ketohydroquinone group. Examples of the nC^6 alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a n- and a third-butoxycarbonyl group. Examples of the "C!-6 alkoxy group" include a decyloxy group, an ethoxy group, and a propoxy group. Examples of ''C^alkyl s(0)a, wherein a is 0 to 2" include sulfonylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methanesulfonyl and The base stone is based on the base. ''C! _6 simmered base' examples include glycerin base and ethyl ketone base. Examples of the nCi-6 alkoxycarbonyl group include a propenyloxy group and an ethoxy group. Examples of the "Ci-6 alkanoylamino group" include a propyl decylamino group and an acetamino group." C2-6 Examples of the alkenyl group include a vinyl group, an allyl group, and a 1-propenyl group. Examples of the "c2_6 alkynyl group" include an ethynyl group, a 1-propynyl group, and a 2-propynyl group. ''N-Cualkyl)amine Examples of the sulfonyl group '' include N-(methyl)amine sulfonyl and N-(ethyl)amine sulfonyl. "Ν,Ν-((^ _6 alkyl)2amine sulfonyl) Examples include hydrazine, fluorenyl-(dimethyl)amine sulfonyl and hydrazine 曱((120858 -16-200811169)-N-(ethyl)amine sulfonyl. "Ν-(ίν6 alkenyl)amine sulfonate Examples of the "base" include fluorenyl-(allyl)amine sulfonyl and fluorenyl-(vinyl)amine sulfonyl. "Ν, Ν-Θ! -6 alkenyl) 2 sulfonamide, an example thereof Including hydrazine, fluorenyl-(diallyl)amine sulfonyl and fluorenyl-(allyl)-fluorenyl-(vinyl)amine sulfonyl."N-(Ch alkyl)amine carbaryl, Examples include methylaminocarbonyl and ethylaminocarbonyl. Examples of 'Ν, Ν-((^_6 alkyl)2-aminocarbamoyl) include dimethylaminocarbonyl and methylethylaminocarbonyl. • 'N-CC! -6 alkenyl) Aminomethyl sulfhydryl Examples of '' include allylaminocarbonyl and vinylaminocarbonyl. Examples of "Ν, Ν·% _6 alkenyl) 2 amine fluorenyl" include diallylaminocarbonyl and (dilyl) (Vinyl)aminocarbonyl. "C!-6 alkylsulfonyl," examples of which include methylsulfonyl and isopropylsulfonyl. "Cii alkenylsulfonyl," examples of which include allyl fluorenyl and vinyl fluorenyl. Examples of sulphur-based sulfhydryl groups include acetophenone acid groups and isopropyl groups. Mercaptoamine group. Examples of the "amino group" include an amidino group and an ethylamine group. Examples of the N,N-(Ci alkyl)2 amine group include a di-N-methylamino group, Di-(N-ethyl)amino group and N_ethyl_N_methylamino group. Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, a salt of a compound of the invention, such as a sodium or potassium salt, an alkaline earth gold, which is sufficiently acidic.

挣檬酸或順丁烯二酸。此外，足 適當藥學上可接受鹽為鹼金屬鹽 屬鹽’例如鈣或鎂鹽，銨鹽， 離子之有機驗之鹽，例如與甲 P比咬、 體内可水解酯，係為 °疋、嗎福啉或參-(2-羥乙基）胺之鹽。 含有綾基或羥基之式①化合物之活, 120858 17- 200811169 例如藥學上可接受之’其係於人類或動物身體中水解， 以產生母體酸或醇。羧基之適當藥學上可接受酯類，包括 Cl-6烷氧基甲基酯類，例如甲氧基甲基，Ci 6烷醯氧基曱基 酯類，例如三甲基乙醯基氧基甲基，酞基酯類，c3 8環烷 氧基羰基氧基q 烷基酯類，例如；μ環己羰基氧基乙基；^3-二氧伍圜烯-2-酮基甲基酯類，例如孓甲基]，3_二氧伍圜烯冬 酮基曱基；及(^_6烷氧羰基氧基乙基酯類，例如丨_甲氧羰基 、氧基乙基，並可於本發明化合物中之任何羧基處形成。 含有羥基之式（I)化合物之活體内可水解酯，包括無機酯 類’譬如磷酸酯類，與α -醯氧基烷基醚類，及相關化合物， 其係由於酯分解之活體内水解之結果，而得母體羥基。心 醯氧基烷基醚類之實例，包括乙醯氧基甲氧基與2,2_二甲基 丙醯氧基-甲氧基。對羥基之活體内可水解酯形成基之選 擇匕括烧酿基、本甲醯基、苯乙醢基，及經取代之苯甲 醯基與苯乙醯基，烷氧羰基（以獲得碳酸烷基酯類）、二烷 基胺甲醯基與Ν-(二烷胺基乙基）_Ν_烷基胺曱醯基（以獲得胺 基甲酸酯類）、二烷胺基乙醯基及羧基乙醯基。於苯甲醯基 上之取代基實例，包括嗎福琳基與六氯七井基，從環氮原 子經由亞甲基連結至苯甲醯基環之3-或4-位置。 一些式（1)化合物可具有對掌中心及/或幾何異構中心（Ε-Μ異構物且應明瞭的是，本發明係涵蓋所有此種具有 CDK抑制活性之光學、非對映異構物及幾何異構物。 本發明係關於具有CDK抑制活性之式(I)化合物之任何及 所有互變異構形式。 120858 18 200811169 亦應明瞭的是，草此 ”二式（I)化合物可以已溶劑化人 溶劑化合形式’例如水合步付/痛0 未 ^ σ形式存在。應明瞭的是，本發明 係涵盍所有此種且右rmr 4 月 有咖抑制活性之溶劑化合形式。Earn citric acid or maleic acid. In addition, a suitable pharmaceutically acceptable salt of the foot is an alkali metal salt, such as a calcium or magnesium salt, an ammonium salt, an organic salt of an ion, for example, a peptide derived from a P, a hydrolyzable ester in the body, A salt of morphine or gin-(2-hydroxyethyl)amine. The activity of a compound of formula 1 containing a thiol or hydroxy group, 120858 17-200811169, for example, pharmaceutically acceptable, is hydrolyzed in a human or animal body to produce a parent acid or alcohol. Suitable pharmaceutically acceptable esters of the carboxy group, including Cl-6 alkoxymethyl esters, such as methoxymethyl, Ci 6 alkyl decyl decyl esters, such as trimethyl acetyl methoxy group Base, mercapto esters, c3 8 cycloalkoxycarbonyloxy q alkyl esters, for example; μ cyclohexylcarbonyloxyethyl; ^3-dioxosin-2-one methyl ester , for example, fluorenylmethyl], 3 dioxolanone, and (^ 6 alkoxycarbonyloxyethyl esters such as hydrazine-methoxycarbonyl, oxyethyl, and Forming at any of the carboxyl groups in the compound of the invention. In vivo hydrolysable esters of the compound of formula (I) containing a hydroxyl group, including inorganic esters such as phosphates, and alpha-nonoxyalkyl ethers, and related compounds, The parent hydroxyl group is obtained as a result of in vivo hydrolysis of ester decomposition. Examples of cardiopuroxyalkyl ethers include ethoxylated methoxy and 2,2-dimethylpropoxy-methoxy The choice of the hydrolyzable ester forming group in the living group of the hydroxyl group includes a calcined base, a methionyl group, a phenethyl group, and a substituted benzamidine group and a phenethyl group, an alkoxycarbonyl group. Obtaining alkyl carbonates), dialkylamine methyl hydrazino groups and fluorenyl-(dialkylaminoethyl)-indole-alkylamine sulfhydryl groups (for obtaining urethanes), dialkylamine B Examples of substituents on the benzylidene group, including the morphine and hexachloro-7, from the ring nitrogen atom via the methylene group to the 3- or 4-benzylidene ring - position. Some of the compounds of formula (1) may have a palm center and/or a geometric isomerization center (Ε-Μ isomers and it is to be understood that the present invention encompasses all such optical, non-pairs having CDK inhibitory activity. The present invention relates to any and all tautomeric forms of a compound of formula (I) having CDK inhibitory activity. 120858 18 200811169 It should also be understood that this is a formula (I) The compound may be present in a solvated human solvated form, such as a hydration step/pain 0 sigma form. It is to be understood that the present invention encompasses all such solvated forms which have a curricidal activity on the right rmr for 4 months.

可變基團之特定咅A 疋思義如下。此種意義可在適當情況下， 伴隨著前文或後文界定夕紅/ 可疋義、請求項或具體實施例 一避便用~ 壤Α為5員飽和雜環，1^ ^ ” 3有一個虱原子與視情況選用 1或2個其他雜原子，選白 好丄 丁 、自N、0或S，其中環八之2個原子 視情況被橋基連接。 環A為6員飽和雜環，其含有一個氮原子與視情況選用之 1或2個其他雜原子’選自N、〇或S;其中環八之2個原子可 視情況被橋基連接。 環A為7員飽和雜環，其含有一個氮原子與視情況選用之 1或2個其他雜原子’選自N、〇或S;其中環蚊2個原子可 視情況被橋基連接。 環A為5或6員飽和雜環，其含有一個氮原子；其中環a 之2個原子可視情況被橋基連接。 環A為5-7員飽和雜環，其含有一個氮原子；其中環八之： 個原子可視情況被橋基連接。 環A為六氫峨咬冰基或四氯峨0各_3_基；其中環八之〕個原 子可視情況被兩個碳原子橋基連接。 裒A為/、氫吡啶_3_基六氫吡啶冬基或四氫吡咯基；其中 環A之2個原子可視情況被一個鍵結或兩個碳原子橋基連 接。 120858 -19- 200811169 環A為一氮七圜烧-3-基、六氫p比唆-3-基、六氫咐* n定基或 四氫吡咯-3-基；其中環A之2個原子可視情況被一個鍵結或 兩個碳原子橋基連接。 環A為六氳P比α定-4-基、四氫P比洛-3-基或8-氮雙環并[3.2.1] 辛各基。 環Α為3-氮雙環并[3.1.0]己烷-3-基、六氫吡啶斗基、六氫吡 啶_4_基、四氫吡咯_3_基或8-氮雙環并[3·2·1]辛-3-基。 環Α為一氮七圜烷-3-基、3-氮雙環并[3.1.0]己烷-3-基、六氫 口比咬-3-基、六氫p比唆-4-基、四氫吨洛-3-基或8-氮雙環并[3.2.1] 辛-3-基。 環A為六氳吡啶冰基、四氫吡咯-3-基或内向各氮雙環并 [3.2.1]辛-3-基。 環A為（1 α，5 α，6 α )-3·氮雙環并[3·1_0]己烷-3-基、（R)-六氫吡 啶-3-基、（S)-六氫吡啶-3-基、六氫吡啶_4_基、四氫吡咯_3·基 或内向-8-氮雙環并[3.2.1]辛-3-基。 環八為一氮七圜烷-3-基、（1〇,5«，6〇：)-3-氮雙環并[3.1.〇]己烷 -3-基、（R)-六氫吡啶各基、（S)-六氫吡啶-3-基、六氫吡啶-4-基、四氫吡咯_3-基或内向_8_氮雙環并[3·2·1]辛-3-基。 R1為氮上之取代基，且係選自氫、（：卜6烷基、Ci-6烷醯基、 胺石黃醯基、Q-6烷氧羰基、q·6烷基磺醯基、（^^烯基磺醯 基或雜環基-R7 ;其中R1可視情況在碳上被一或多個R8取 代；其中 R7 為·(：(0); R8係選自鹵基、羥基、Cu烷基、Cu烷氧基、Ν-((ν6烷 120858 -20· 200811169 基）胺基、碳環基-R17-或雜環基机：其中r8可視情況在碳 上被一或多個R19取代；且其中若該雜環基含有_^_部份基 團，則該氮可視情況被選自R2〇之基團取代； R20係選自Ch烧基或Cb6燒氧幾基；其中r20可視情況在 碳上被一或多個R2 1取代； R17與R18為直接鍵結；且 R19與R21係獨立選自羥基與甲氧基。 R1為氮上之取代基，且係選自氫、Ci 6烷基、Ci 6烷醯基、 胺曱醯基、N-Cq_6烷基）胺甲醯基、N，N-(Ci_6烷基）胺甲醯基、 胺石黃醯基、Ν-Α _6烷基）胺磺醯基、ν,Ν-Α _6烷基）2胺磺醯 基、q — 6烷氧羰基、C^6烷基磺醯基、（^^烯基磺醯基或雜 環基-R7 ;其中R1可視情況在碳上被一或多個R8取代；且其 中若該雜環基含有-ΝΉ-部份基團，則該氮可視情況被選自 R9之基團取代； R7係選自-C(O)-、-C(0)N(R15)·、-s(0)2-或-S02N(R16)-;其中 R15與R1 6為氫； R8係選自鹵基、硝基、羥基、胺基、Cl_6烷基、Cl 6烷氧 基、N-(Ch烷基）胺基、Ν，Ν·((ν6烷基）2胺基、碳環基-Ri7_ 或雜環基-R18-;其中R8可視情況在碳上被一或多個Ri9取 代；且其中若該雜環基含有-Ml·部份基團，則該氮可視情 況被選自R2 G之基團取代； R9與R2G係獨立選自C〗_6烷基、CV6烷醯基、CV6烷氧羰基 及苄氧羰基；其中R9與R2G可互相獨立地視情況在碳上被一 或多個R21取代； 120858 -21 - 200811169 R17與R18係獨立選自直接鍵結或_N(R22)_;其中R22係選自 氳或CV6烧基；且 R19與R21係獨立選自鹵基、氰基、羥基、胺甲醯基、甲 基、丙基、環丙基及甲氧基。 R1為氮上之取代基，且係選自氫、甲基、乙基、丙基、 異丙基、乙醯基、丙醯基、丁醯基、胺磺醯基、甲氧羰基、 乙氧幾基、第三-丁氧羰基、甲烷磺醯基、乙基磺醯基、丙 基磺醯基、乙烯基磺醯基或六氫吡啶基-R7 ;其中R1可視情 況在碳上被一或多個R8取代；其中 R7 為-C(O)-; R8係選自氣基、羥基、曱基、甲氧基、乙胺基、異丙基 胺基、丙胺基、丁 -2-基胺基、第三_丁基胺基、3_甲基丁 基胺基、苯基-R17-、六氫吡畊基·Ri8·、六氫吡啶基-Ris一、 嗎福啉基-R1或四氫吡咯基_Ri8·;其中R8可視情況在碳上 被一或多個R19取代；且其中該六氫吡啶基或六氫吡畊基可 視情況在氮上被選自R2〇之基團取代； R20係選自曱基、乙基或第三-丁氧羰基；其中R2〇可視情 況在碳上被一或多個R2 1取代； R17與R18為直接鍵結；且 R19與R21係獨立選自羥基與甲氧基。 R1為氮上之取代基，且係選自氫、甲基、乙基、丙基、 異丙基、乙醯基、丙醯基、丁醯基、胺甲醯基、N_甲基胺 甲醯基、N-乙基胺甲醯基、N，N-二甲基胺甲醯基、胺磺醯基、 N-乙基胺磺醯基、N-丙基胺磺醯基、N-(2,2-二甲基丙基）胺碏 120858 -22- 200811169 醯基、N-甲基-N-丙基胺績醯基、N，N-二甲基胺石黃酿基、甲氧 羰基、乙氧羰基、第三-丁氧羰基、甲烷磺醯基、乙基磺醯 基、丙基續醯基、3-甲基丁基磺醯基、乙烯基磺醯基、嗎 福啉基_R7、高六氫吡畊基-R7、六氫吡畊基_R7、四氫吡咯 基-R7或六氫吡啶基-R7 ;其中R1可視情況在碳上被一或多個 R8取代，且其中該嗎福琳基、咼六氫峨p井基、六氫p比p井基、 六氫峨唆基或四氫吡咯基可視情況被選自R9之基團取代； R7係選自-C(O)-、-C(0)N(R15)-、-S(0)2_4-S02N(R16)-;其中 R15與R1 6為氫； R8係選自氣基 '硝基、經基、胺基、曱基、甲氧基、 甲胺基、N-乙胺基、N-丙基胺基、N-異丙基胺基、N-丁 -2_ 基胺基、3-曱基丁 -2-基胺基、2_甲基丙基胺基、Ν，Ν-二曱 胺基、Ν，Ν-二乙胺基、Ν-甲基乙胺基、Ν-甲基-N-異丙基胺 基、環戊基-R17-、環丁基-Ri、、環丙基_Ri7_、苯基-Ri7… 嗎福淋基-R1 8 _、高嗎福啉基_Ri8 -、硫代嗎福啉基_Ri8 —、高 硫代嗎福啉基-R18 -、六氫吡啶基_Ri8 _、'氮雙環并[2.21]庚 基-R18_、2-氮雙環并[2.2.2]辛基-Ri 、6-氮雙環并[2·2.2]辛基 -R18·、一氮四圜基-Ri8_、四氫吡咯基_Rl8_、酮基六氫吡 畊基-R18_、2_酮基高六氫吡畊基_Ri 8_、高六氫吡啩基-Ri 8_ 或六氫吡畊基-R1 8 -;其中R8可視情況在碳上被一或多個r1 9 取代；且其中該高六氫吡畊基、四氫吡咯基、六氫吡畊基 或六氫峨啶基可視情況在氮上被選自R2 〇之基團取代； R9與R2〇係獨立選自曱基、乙基、異丙基、乙醯基、第三 -丁氧羧基及苄氧羰基；其中R9與R2 〇可互相獨立地視情況 120858 -23 · 200811169 在碳上被一或多個R2 1取代； R與R18係獨立選自直接鍵結4_N(R22)_;其中R22係選自 氫或甲基；且 R19與R21係獨立選自氤基、氰基、羥基、胺曱醯基、甲 基、丙基、環丙基及甲氧基。 R1為氮上之取代基，且係選自氫、甲基、丙基、異丙基、 乙烯基石黃酸基、曱烷磺醯基、苄氧羰基、第三-丁氧羰基、 乙酿基、苯乙基、乙氧羰基、2-甲氧基乙基、胺磺醯基、 爷基、3-氣基丙基磺醯基、3_(2_曱氧基乙胺基）丙基磺醯基、 3-經丙基磺醯基、3_(1_羥丙冬基胺基）丙基磺醯基、3-(1-甲基 六氫峨畊冰基）丙基磺醯基、羥乙基）六氫吡畊斗基]丙 基確醯基、3-四氫吡咯小基丙基磺醯基、3_嗎福啉基丙基磺 醯基、3-(1-羥基丁 _2·基胺基）丙基磺醯基、3-(1-甲氧基丙-2-基胺基）丙基磺醯基、3-(2-羥丙基胺基）丙基磺醯基、3_(1_羥 基-3-甲基丁冬基胺基）丙基磺醯基、4-嗎福啉基丁醯基、3-(1-Μ基甲基丙_2_基胺基）丙基磺醯基、3-(六氳吡啡-4-基）丙醯 基、2-(1-甲基六氫吡畊_4_基）乙基磺醯基、2_四氫吡咯小基乙 基磺醯基、2-(2-甲氧基乙胺基）乙基磺醯基、2_(]μ第三_丁氧 幾基六氫吡啶-4-基）乙醯基、3-(1-第三-丁氧羰基六氫吡畊_4_ 基）丙醯基、2-(六氫吡啶-4-基）乙醯基、3-(1-第三-丁氧羰基六 氲p比咬-4-基）丙酸基、2-(1-第三-丁氧幾基六氫p比σ定-3-基）乙醯 基、1·第三-丁氧羰基-4-甲基六氫吡啶斗基羰基、3·(六氫吡 咬-4-基）丙醯基、4-甲基六氫吡啶-4-基羰基及2-(六氫吡啶-3-基）乙醯基。 120858 -24- 200811169 R1為氮上之取代基，且係選自氫、甲基、丙基、異丙基、 乙烯基磺醯基、曱烷磺醯基、芊氧羰基、第三_丁氧羰基、 乙醯基、苯乙基、乙氧羰基、2-甲氧基乙基、胺磺醯基、 N，N-二甲基胺磺醯基、ν,ν—二甲基胺甲醯基、苄基、胺甲醯 基、N-甲基胺甲醯基、2_(二曱胺基）乙基磺醯基、2_(N•甲基| 異丙基）乙基績醯基、2-(1-甲基六氫外-4-基）乙基磺醢基、 2-四氫吡咯小基乙基磺醯基、2-(3·氟基四氫吡咯-1-基）乙基磺 醯基、2-(硫代嗎福啉-4-基）乙基磺醯基、2-(4-曱基六氫吡啶-1-基）乙基續醯基、2-(高六氫p比咬-1-基）乙基績酸基、2-二乙胺 基乙基磺醯基、2·—氮四圜-1-基乙基績醯基、2-嗎福淋基乙 基磺醯基、2-(4-氟基六氫吡啶小基）乙基磺醯基、2-(4-氰基六 氫外I：咬-1-基）乙基績醯基、2-(4-丙基六氫p比唆小基）乙基續醯 基、2-(4-胺甲醯基六氫吡啶小基）乙基磺醯基、2-(7-氮雙環并 [2·2·1]庚-7-基）乙基磺醯基、2-(2-氮雙環并[2.2.2]辛-2·基）乙基磺 醯基、2-(6•氮雙環并[2.2.2]辛-6-基）乙基磺醯基、2-高嗎福啉基 乙基磺醯基、2-(2-酮基六氫吡畊冰基）乙基磺醯基、2-(1-乙醯 基六氫吡畊-4-基）乙基石黃醯基、2-(2-甲氧基乙胺基）乙基磺醯 基、2-(N-甲基_N-環丙基）乙基磺醯基、2-(2-酮基高六氫吡畊-4-基）乙基磺醯基、2-(1-乙醯基高六氫吡畊-4-基）乙基磺醯基、 2- (N-曱基-N-環丙基甲基）乙基磺醯基、2_(高硫代嗎福琳_4_基） 乙基磺醯基、3-氯基丙基磺醯基、3-二甲胺基丙基磺醯基、 3- 二甲胺基-2,2-二甲基丙基磺醯基、3-二乙胺基丙基磺醯基、 3-(2-甲氧基乙胺基）丙基磺醯基、3-[N-甲基_N-(2-甲氧基乙基） 胺基]丙基磧醯基、3·經丙基績醯基、3-(1-經丙-2-基胺基）丙 120858 -25- 200811169 基〜Si&基、3-(1-甲基六氫吡畊_4-基）丙基續醯基、3-(1_異丙基 六氫吡畊-4_基）丙基磺醯基、3_(6_氮雙環并[2 2 2]辛_6-基）丙基 石男基、3-(7-氮雙環并[2·2·1]庚_7_基）丙基磺醯基、3-[i-(2-經乙 基）六氫峨畊-4-基]丙基磺醯基、3_四氫吡咯_ι_基丙基磺醯基、 3 (1’4 一甲基四氲咐洛小基）丙基績醯基、3-嗎福琳基丙基石黃 隨基、3-(1_羥基丁 _2_基胺基）丙基磺醯基、3_(1_甲氧基丙_2_ 基胺基）丙基磺醯基、3-(2-羥丙基胺基）丙基磺醯基、^⑴羥 基-3-曱基丁 -2-基胺基）丙基磺驢基、3-(1-經基-2-甲基丙-2_基胺 基）丙基磺醯基、3-(六氫吡啶小基）丙基磺醯基、3-(環丙胺基） 丙基績醯基、3-(N-甲基-N-環丙胺基）丙基磺醯基、3-(環戊基 胺基）丙基磺醯基、3-(N-甲基環戊基胺基）丙基磺醯基、 Η環丁基胺基）丙基續醯基、3_(N-曱基-N-環丁基胺基）丙基石黃 醯基、3-(異丙基胺基）丙基磺醯基、3-(N-甲基-N-異丙基胺基） 丙基石κ 基、3-(N-曱基-N-乙胺基）丙基石黃酿基、3-[N-甲基-N-(2_ 氰基乙基）胺基]丙基磺醯基、3-[N-乙基-N-(2-氰基乙基）胺基] 丙基績酿基、3-—氣四圜-1-基丙基石黃酿基、3_(環丙基甲胺基） 丙基磺醯基、3-(N-曱基-N-環丙基甲胺基）丙基磺醯基、3_硝 基-3-甲基丁基績贐基、3-胺基-3-甲基丁基石黃酿基、3-二曱基 •3·甲基丁基績醯基、2-(六氫叶b咬_3_基）乙醯基、2-(1-第三-丁 氧羰基六氫吡啶-3-基）乙醯基、2-(六氫吡啶-4-基）乙醯基、2-(1-第三-丁氧羰基六氫吡啶冰基）乙醯基、2_二甲胺基乙醯基、 3-(1_第三-丁氧羰基六氫吡4 -4-基）丙醯基、3-(1-第三-丁氧魏 基六氫p比咬-4-基）丙醢基、3-(六氫p比咬-4-基）丙醯基、3-(六氫 吡啩-4-基）丙醯基、3-二甲胺基丙醯基、4_嗎福p林基丁醯、4- 120858 -26- 200811169 二甲胺基丁醯基、ι_第三-丁氧羰基斗甲基六氫吡啶斗基羰 基、4-甲基六氫叶1:咬_4·基羰基、μ第三·丁氧羰基斗甲基六氫 吡啶斗基羰基、4-甲基高六氫吡畊小基羰基、μ甲基六氫吡 咬-3-基羰基、1-甲基四氫吡咯冬基羰基、3-二甲胺基四氫吡 洛-1-基幾基、4-第三·丁氧羰基嗎福啉_2_基羰基、嗎福啉_2· 基幾基' 1-甲基六氫吡啶-4-基胺甲醯基、Ν_(μ乙基四氫吡咯 -2-基甲基）胺甲醯基、Ν-(2-四氫峨洛小基乙基）胺甲醯基、ν_(2_ 一甲胺基乙基）胺甲醯基' N-(l-甲基六氫ρ比唆冰基）胺石黃醯 基、N-(l-異丙基六氫ρ比σ定-4-基）胺石黃醯基、2_(二甲胺基）乙基 胺磺酿基、2-(二乙胺基）乙基胺磺醯基、2-(嗎福淋基）乙基胺 石頁醯基、2-(1-甲基六氫吡畔冰基）乙基胺磺醯基、2-(1-甲基四 氫咐咯1基）乙基胺磺醯基、3-(四氫吡咯_ι_基）丙基胺磺醯 基、3_(3-氟基四氫吡咯小基）丙基胺磺醯基、3_二曱胺基_2,2· 一甲基丙基胺磺醯基、3-(六氫吡啶-1-基）丙基胺磺醯基、N-甲基1(3-二甲胺基丙基）胺磺醯基、3_二甲胺基四氫吡咯小 基石頁酿基、i-甲基六氫吡畊-4-基磺醯基、1-甲基六氫吡啶_4_ 基石頁醢基、μ異丙基六氫吡啶-4-基磺醯基及μ甲基高六氫吡 11 井_4_基磺醯基。 q為0 〇 R3為_基。 R為鼠基或氣基。 η為〇 〇 η為1 〇 η為0或1。 120858 -27- 200811169 R4為異丙基。 R4為環戊基。 R4係選自異丙基或環戊基。 R5為甲基。 5衣A，Ri，R2及q—起形成1-乙龜基-4-六鼠^比σ定基、1-乙酿基 四氫外b σ各-3-基、1-苄基-4-六氫外b咬基、1_苄氧幾基-4-六氫外匕 啶基、1-胺甲醯基-4-六氫吡啶基、1-乙氧羰基-4-六氫吡啶基、 1-異丙基-4-六氫吡啶基、1_甲基-4-六氫吡啶基、1-甲磺醯基 -4-六氫峨咬基、1-甲石黃醯基四氫u比洛-3-基、1-苯乙基-4-六氫 外匕σ定基、1-丙基-4-六氮p比唆基、1-胺績S盛基-4-六氯p比σ定基、 1-胺磺醯基四氫吡咯-3-基、1-第三-丁氧羰基-4-六氫吡啶基、 1-第三-丁氧羰基四氫吡咯-3·基、1-乙烯基磺醯基-4-六氫吡啶 基、（lR，5S)-3-(2-二甲胺基乙基磺醯基）-3-氮雙環并[3.1.0]己-6-基、（lR，5S)-3-(2-四氫吡咯-1-基乙基磺醯基）-3-氮雙環并[3丄〇] 己-6·基、（lR，5S)-3-(3-二甲胺基丙基磺醯基）-3-氮雙環并[3丄〇] 己-6-基、（lR，5S)-3_(3·四氮ρ比洛-1-基丙基績酿基）_3-氮雙環并 [3.1.0]己-6-基、（lR，5S)-3-[2-(7·氮雙環并[2.2.1]庚-7-基）乙基磺醯 基]士氮雙環并[3.1.0]己-6_基、（lR，5S)-3-[3-(l-六氫吡啶基）丙基 磺醯基]-3-氮雙環并[3.1_0]己-6-基、（lR，5S)-3-[3-(2,5-二甲基四氫 吡咯-1-基）丙基磺醯基]-3-氮雙環并[3丄0]己-6-基、（lRjSp-Ka-氮 雙環并 [2·2·1] 庚 -7-基）丙基磺 醯基]-3-氮 雙環并 [3.1.0] 己 各基、（lR，5S)-3-[3-(環戊基·曱基-胺基）丙基磺醯基]_3·氮雙環并 [3·1·〇]己-6-基、（lR，5S)-3_氮雙環并[3.1.0]己-6-基、（lR，5S)-3-爷氧 羰基-3_氮雙環并[3·1·0]己-6-基、（lR，5S)-3-甲磺醯基-3-氮雙環并 120858 -28- 200811169 [3·1·0]己各基、（1R，5S)各甲基-8-氮雙環并[3.2.1]辛-3_基、（3R)-1-甲磺醯基-3-六氫吡啶基、（3R)小第三-丁氧羰基-3-六氫吡啶 基、（3R)-3-六氫p比淀基、（3S)-1-甲石黃醯基-3-六氫外1：咬基、（3S)-1-第三-丁氧羰基-3-六氫吡啶基、（3S)-3-六氫吡啶基、1-(1-甲基 六鼠p比咬-3-魏基）-4-六鼠p比σ定基、1-(1-甲基四氮p比略-2-幾 基）-4-六氮？比σ定基、二乙胺基乙基胺石黃酿基）-4-六氮p比。定 基、1-(2-二乙胺基乙基績S篮基）-4-六氫外b σ定基、1-(2-二甲胺基 乙醯基）-4-六氫吡啶基、1-(2-二甲胺基乙基胺甲醯基>4-六氫 吡啶基、1-(2-二甲胺基乙基胺甲醯基）四氫吡咯-3-基、1-(2-二甲胺基乙基胺石黃酿基）-4-六氮ρ比唆基、1-(2-二甲胺基乙基 石黃龜基）-4-六氮批σ定基、1-(2-甲氧基乙基）-4-六氣？比σ定基、1-(2_ 嗎福淋基乙基胺石黃酿基）-4-六氮ρ比咬基、1-(2-嗎福ρ林基乙基 磺醯基）-4-六氫吡啶基、1-(2-四氫吡咯-1-基乙基胺甲醯基）-4-六氮p比唆基、1-(2-四鼠外b洛-1-基乙基胺石黃酿基）-4-六氮p比σ定 基、1-(2_四氮ρ比哈-1-基乙基績酿基）-4-六鼠说σ定基、1-(2-硫代 嗎福p林基乙基石黃酸基）-4-六氮ρ比咬基、1-(3-胺基-3-曱基-丁基） 石黃醢基-4-六氫叶1： σ定基、1-(3-氯基丙基石黃醯基）-4_六氫p比π定 基、1-(3-氣基丙基磧醯基）四氫吡咯-3-基、1-(3-二乙胺基丙基 磺醯基）-4-六氫吡啶基、1-(3-二甲胺基-3-甲基-丁基）績醯基-4_ 六氫吡啶基、1-(3-二甲胺基丙醯基）-4-六氫吡啶基、1-(3-二甲 胺基丙基-甲基-胺磺醯基）-4-六氫吡啶基、1-(3-二甲胺基丙基 石黃醯基）-4-六氫说17定基、1-(3-經丙基石黃醯基）-4-六氫p比咬基、 1-(3-甲基·3-硝基-丁基）確醯基斗六氫吡啶基、H3-嗎福啉基丙 基磺醯基）-4-六氫吡啶基、1-(3·六氫吡畊小基丙醯基）-4·六氫 120858 -29- 200811169 外匕咬基、1-(3-六氫外-1-基丙醯基）四氫峨洛-3-基、1-(3-四氫 吡咯小基丙基胺磺醯基）-4-六氫吡啶基、1-(3-四氫p比咯小基 丙基磺醯基）-4-六氫吡啶基、1-(3-四氫吡咯小基丙基磺醯基） 四鼠p比洛-3-基、1-(4-二甲胺基丁酿基）-4-六氮p比σ定基、ι_(4_ 甲基-1，4-二氮七圜烷小羰基）-4-六氫吡啶基、1-(4-甲基小第三 -丁氧羰基-六氫吡啶-4-羰基）冰六氫吡啶基、1-(4-甲基小第三 -丁氧羰基-六氫吡啶斗羰基）四氫吡咯-3-基、1-(4-甲基六氫吡 _ -1-基）磺醯基-4-六氫叶t» σ定基、1-(4-甲基六氫外b °定-4-幾基）-4-六氫吡啶基、1-(4-甲基六氫吡啶-4·羰基）四氫吡咯各基、1-(4-嗎福啉基丁醯）-4-六氫吡啶基、1-(4-六氫吡啶基磺醯基）-4-六 氮口比σ定基、1_(4_第三-丁乳織基嗎福琳-2-織基）-4-六款p比咬 基、1·(二甲基胺甲醯基）-4-六氫吡啶基、1-(二甲基胺磺醯 基）-4-六氫叶1：咬基、1-(甲基胺甲醯基）-4-六氫p比淀基、1-(甲基 胺甲醯基）四氫吡咯-3-基、1-(嗎福啉-2-羰基>4-六氫吡啶基、 1-[(1_芊氧羰基；六氫吡啶基）甲磺醯基]冰六氫吡啶基、1-[(1_ 苄氧羰基-4-六氫吡啶基）石黃醯基]-4-六氫吡啶基、μ[(1-異丙基 -4-六氫吡啶基）胺磺醯基六氫吡啶基、1-[(1-異丙基-4-六氫 口比σ定基）石黃醯基]-4_六氫叶1:σ定基、1-[(1-甲基-4-六氫p比唆基）胺甲 醯基]冰六氫峨咬基、1-[(1_甲基-4-六氫ρ比咬基）胺石黃醢基]-4-六氫峨唆基、1-[(1-甲基-冬六氫外b ϋ定基）石黃醯基]-4-六氫ρ比咬 基、1-[(3-二甲胺基-2,2-二甲基-丙基）胺石黃酿基]-4-六氯ρ比。定 基、1-[(3R)_3-二甲胺基四氫吡咯-1-基]磺醯基-4-六氫吡啶基、 l-[(3S)-3-二甲胺基四氫吡咯-1-羰基]-4-六氫吡啶基、1-[(4·甲基 -1，4-二氮七圜烷小基）石黃醯基H-六氫吡啶基、1-[[(2R)小乙基四 120858 -30- 200811169 氫吡咯-2-基]甲基胺曱醯基]冰六氫吡啶基、^哎外丨·乙基四 氫峨洛-2-基]甲基胺甲醯基]冰六氳吡啶基、1-[2_(1，4_氧氮七圜 f -4-基）乙基磺醯基]冰六氫吡啶基、^[2-(1,4-硫氮七圜冰基）乙 基磺醯基]-4_六氫吡啶基、μρχμ甲基四氫吡咯_2-基）乙基胺 磺醯基]-4-六氫吡啶基、六氫吡啶基）乙基磺醯基]冰六 氫吡啶基、1_[2-(1-第三-丁氧羰基斗六氫吡啶基）乙醯基]冬六 氫叶1：σ定基、1-[2-(1-第三-丁氧魏基-4-六氫批咬基）乙醯基]四氫 吡咯-3-基、1-[2-(2-曱氧基乙胺基）乙基磺醯基]_4_六氫吡啶基、 1Κ3-酮基六氫吡畊小基）乙基石黃醯基]冰六氫吡ϋ定基、1Κ4-乙酿基-1，4-一氮七圜烧小基）乙基石黃酿基]_4_六氫ρ比σ定基、 1-[2-(4-乙醯基六氫吡哺小基）乙基磺醯基>4-六氫吡啶基、 1-[2-(4-胺甲醯基-1_六氫吡啶基）乙基磺醯基]_4_六氫吡啶基、 1-[2-(4-氰基-1·六氳吡啶基）乙基磺醯基]_4_六氫吡啶基、ι_[2-(4-氟基-1-六氫吡啶基）乙基磺醯基]·4-六氫吡啶基、1-[2-(4-甲基 小六氫外1： σ定基）乙基石黃醢基]-4·六氫ρ比π定基、ΐ-[2-(4-甲基六氫 叶匕ρ井-1-基）乙基胺績酿基]-4-六氫峨σ定基、ΐ-[2-(4-曱基六氛外匕 畊_1_基）乙基磺醯基]-4-六氫吡啶基、l-[2-(4-六氫吡啶基）乙醯 基]斗六氯说咬基、1-[2-(4-六氫ρ比咬基）乙酿基]四氫p比洛-3-基、1-[2-(4-丙基-1-六氫吡啶基）乙基磺醯基]-4-六氫吡啶基、 1-[2-(5-氧基，酮基-1，4-二氮七圜烷-1-基）乙基磺醯基]冰六氫吡 啶基、1-[2-(7-氮雙環并[2·2·1]庚·7_基）乙基磺醯基]-4-六氫吡啶 基、1-[2-(8-氮雙環并[2·2·2]辛-8-基）乙基續醯基]-4-六氫批σ定基、 1-[2-(—氮四圜-1-基）乙基磺醯基]-4-六氫吡啶基、1-[2-(環丙基 -甲基-胺基）乙基磺醯基Η·六氫吡啶基、1_[2-(環丙基甲基-甲 120858 -31 - 200811169 基-胺基）乙基績醯基]-4-六氫P比π定基、1_[2_(異丙基_甲基-胺基） 乙基續醯基]冰六氫峨啶基、；第三_丁氧羰基各六 氫外1：唆基]乙酸基]冰六氫吡啶基、i_[2-[(3R)小第三-丁氧羰基 -3-六氫说唆基]乙醯基]四氫吡咯_3_基、氟基四氫 外匕洛-1-基]乙基磺醯基]-4-六氫吡啶基、各六氫吡啶 基]乙醯基]-4-六氫吡啶基、H2-[(3R)_3_六氫吡啶基]乙醯基] 四氫吡咯-3-基、l-[2-[(3S)小第三-丁氧羰基_3_六氫吡啶基]乙醯 基]冰六氫p比啶基、l-[2-[(3S)_l-第三-丁氧羰基_3_六氫吡啶基] 乙醯基]四氫吡咯-3-基、l_[2-[(3S)-3-氟基四氫吡咯小基]乙基磺 醯基]-4-六氫叶b π定基、i_[2-[(3S)-3-六氫p比咬基]乙醯基]_冬六氫 吡啶基、l-[2-[(3S)-3-六氫吡啶基]乙醯基]四氫吡咯_3-基、 1-[3-(1-六氫吡啶基）丙基胺磺醯基]_4_六氫吡啶基、六氫 吡啶基）丙基績醯基]冰六氫吡啶基、1-[3-(1_第三_丁氧羰基-4-六氫外b咬基）丙醢基]-4-六氫p比σ定基、第三_丁氧幾基_4_ 六氫吡啶基）丙醯基]四氫吡咯-3-基、1-[3-(2-氰基乙基-乙基-胺基）丙基績醯基]-4-六氫吡咬基、l-[3-(2-氰基乙基-甲基-胺 基）丙基續醯基]-4-六氫ρ比咬基、l-[3-(2-經丙基胺基）丙基石黃酸 基]-4-六氫吡啶基、1-[3-(2-甲氧基乙胺基）丙基磺醯基]_4_六氫 外匕σ定基、1-[3-(2-甲氧基乙胺基）丙基績隨基]四氫ρ比洛_3-基、 1-[3-(2_甲氧基乙基-甲基-胺基）丙基績酿基]六氮ρ比t?定基、 1-[3-(4-異丙基六鼠p比p井小基）丙基績酿基]四氮p比洛_3_基、 卜[3-(4-甲基六氫吡畊小基）丙基磺醯基]_4_六氫吡啶基、i-[3-(4-甲基六氫吡畊-1-基）丙基磺醯基]四氫吡咯_3_基、l-[3-(4-六氫 口比σ定基）丙醢基]-4-六氫P比唆基、1-[3-(4_六氫峨cr定基）丙醢基] 120858 -32- 200811169 四氫吡咯士基、H3-(4-第三_丁氧羰基六氫吡畊·丨_基）丙醯 基]冰六氫吡啶基、^[3-(44三-丁氧羰基六氳吡畊小基）丙醯 基]四氫晚洛-3-基、1-[3-(7-氮雙環并[2.2.1]庚-7-基）丙基磺醯 基H·六氫吡啶基、1-[3普氮雙環并[2 2·2]辛各基）丙基磺醯 基]-4-六氫吡啶基、一氮四圜+基）丙基磺醯基]冬六氫吡 11疋基' 1-[3-(環丁基胺基）丙基磺酿基]_4_六氫说σ定基、環 丁基-甲基-胺基）丙基磺醯基]_4_六氫吡啶基、(環戊基胺 基）丙基磺醯基Η-六氫吡啶基、丨#·(環戊基_甲基-胺基）丙基 磺醯基]冰六氫吡啶基、H3_(環丙胺基）丙基磺醯基]_4_六氫吡 咬基、1-[3_(環丙基曱胺基）丙基磺醯基]_4_六氫吡啶基、 ^[3-(環丙基-甲基-胺基）丙基磺醯基]冰六氫吡啶基、(環 丙基甲基-甲基-胺基）丙基磺醯基]冰六氫吡啶基、丨_[3_(乙基_ 甲基-胺基）丙基磺醯基]-4_六氫吡啶基、μ[3_(異丙基胺基）丙 基續酿基Η-六氫吡啶基、；μρ-(異丙基_甲基_胺基）丙基磺醯 基>4-六氫吡啶基、羥基二甲基_乙基）胺基]丙基磺 醯基]+六氫吡啶基' H3-[(2-羥基小甲基-乙基）胺基]丙基磺 醯基六氫吡啶基、H3-[(2-甲氧基-1-甲基-乙基）胺基]丙基 磺醯基]冰六氫吡啶基、H3-[(3S)-3-氟基四氫吡咯小基]丙基胺 磺醯基M-六氫吡啶基、HH[1_(羥甲基）-2_甲基_丙基]胺基] 丙基磺醯基]-4_六氫吡啶基、H；H1_(羥甲基）丙胺基]丙基磺醯 基]-4-六氯峨σ定基、1-[3-[冬(2•羥乙基）六氫吡畊小基]丙基磺醯 基>4-六氫吡啶基、4_六氫吡啶基、一氮七圜烷_3_基、四氫 口比各-3-基及1-(第三_丁氧羰基）一氮七圜烷_3_基。 因此，於本發明之進一步方面，係提供式（I)化合物（如上 120858 -33- 200811169 文所描繪），其中： 環A為5或6員飽和雜環，其含有一個氮原子；其中環a 之2個原子可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Ci4烷基、烷醯基、 胺石黃酸基、Cl_6烧氧幾基、Ch烧基確醯基、稀基確酿 基或雜環基-R7 ;其中Ri可視情況在碳上被一或多個圮取 代； q為0 ; η為〇 ; R4為異丙基； R5為甲基； R7 為-C(o)-; R8係選自•基、羥基、Cl_6烷基、Ci 6烷氧基、n_(Ch烷 基）胺基、破環基-R'或雜環基pR8可視情況在碳 上被或夕個R19取代；且其中若該雜環基含有_祕部份基 團，則該氮可視情況被選自R2〇之基團取代； R係選自c^6烷基或c1-0烷氧羰基；其中R2〇可視情況在 石厌上被一或多個R2 1取代；The specific 咅A of the variable group is as follows. Such a meaning may be circumscribed in the appropriate circumstances, along with the definition of the previous or subsequent suffix, the request item or the specific example - the soil is a 5-member saturated heterocyclic ring, 1 ^ ^ ” 3 has a The ruthenium atom and 1 or 2 other heteroatoms are selected as appropriate, and the ruthenium is selected from N, 0 or S, wherein the two atoms of the ring VIII are connected by a bridging group as the case may be. The ring A is a 6-member saturated heterocyclic ring. It contains a nitrogen atom and optionally 1 or 2 other heteroatoms selected from N, hydrazine or S; wherein 2 atoms of the ring VIII are optionally joined by a bridging group. Ring A is a 7-membered saturated heterocyclic ring. Containing a nitrogen atom and optionally 1 or 2 other heteroatoms selected from N, hydrazine or S; wherein 2 atoms of the cyclospores may optionally be joined by a bridging group. Ring A is a 5 or 6 member saturated heterocyclic ring, Containing a nitrogen atom; wherein two atoms of ring a may be optionally joined by a bridging group. Ring A is a 5-7 membered saturated heterocyclic ring containing a nitrogen atom; wherein the ring: each atom may be attached by a bridging group. Ring A is a hexahydro hydrazine or an octachloroquinone 0 _3 _ group; wherein the atom of the ring VIII can be bridged by two carbon atoms裒A is /, hydropyridine _3_ hexahydropyridinyl or tetrahydropyrrolyl; wherein two atoms of ring A may be bonded by one bond or two carbon atom bridges. 120858 -19- 200811169 Ring A is a nitrogen heptasulfon-3-yl group, a hexahydrop-pyrimidin-3-yl group, a hexahydroquinone* n group or a tetrahydropyrrol-3-yl group; wherein the two atoms of ring A may be one by one Bonding or linking of two carbon atom bridging groups. Ring A is a hexamidine P ratio α-1,4-yl, tetrahydro-Pbi-3-yl or 8-azabicyclo[3.2.1] octyl. Α is 3-azabicyclo[3.1.0]hexane-3-yl, hexahydropyridyl, hexahydropyridinyl-4-yl, tetrahydropyrrole-3-yl or 8-azabicyclo[3·2 · 1] oct-3-yl. Cyclopurine is nitros-7-yl-3-yl, 3-azabicyclo[3.1.0]hexane-3-yl, hexahydro-n-butyl-3-yl, six Hydrogen p is more than 唆-4-yl, tetrahydro-ton-3-yl-3- or 8-azabicyclo[3.2.1]oct-3-yl. Ring A is hexafluoropyridyl ice-based, tetrahydropyrrol-3-yl Or inwardly each nitrogen bicyclo[3.2.1]oct-3-yl. Ring A is (1 α,5 α,6 α )-3·azabicyclo[3·1_0]hexane-3-yl, (R )-hexahydropyridin-3-yl, (S)-hexahydropyridin-3-yl, hexahydropyridine_4_ , tetrahydropyrrole _3·yl or inward-8-azabicyclo[3.2.1]oct-3-yl. Cyclooctyl is nitros-7-yl-3-yl, (1〇, 5«, 6〇: )-3-azabicyclo[3.1.〇]hexane-3-yl, (R)-hexahydropyridine, (S)-hexahydropyridin-3-yl, hexahydropyridin-4-yl, tetra Hydropyrrole-3-yl or inward _8-azabicyclo[3·2·1]oct-3-yl. R1 is a substituent on the nitrogen and is selected from hydrogen, (: 6 alkyl, Ci-) 6 alkyl fluorenyl, amine fluorenyl, Q-6 alkoxycarbonyl, q. 6 alkylsulfonyl, (^^ alkenylsulfonyl or heterocyclyl-R7; wherein R1 may be taken on carbon by one or Substituted by a plurality of R8; wherein R7 is ·(:(0); R8 is selected from the group consisting of a halogen group, a hydroxyl group, a Cu alkyl group, a Cu alkoxy group, a fluorene-((ν6 alkane 120858 -20· 200811169) amine group, carbon a cyclo-R17- or heterocyclic machine: wherein r8 may be optionally substituted on the carbon with one or more R19; and wherein if the heterocyclic group contains a moiety, the nitrogen may optionally be selected from R2 is substituted with a group; R20 is selected from a group consisting of a Ch group or a Cb6 alkoxy group; wherein r20 may be optionally substituted with one or more R2 1 on the carbon; R17 and R18 are directly bonded; and R19 and R21 are Li is selected from hydroxy and methoxy. R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, Ci 6 alkyl, Ci 6 alkyl fluorenyl, amine fluorenyl, N-Cq-6 alkylamine carbhydryl, N,N-(Ci_6 alkyl) Aminomethyl sulfhydryl, amine fluorenyl, hydrazine-hydrazine -6 alkyl sulfonyl, ν, Ν-Α -6 alkyl) 2 amine sulfonyl, q-6 alkoxycarbonyl, C 6 alkyl sulfonium Or (^^ alkenylsulfonyl or heterocyclyl-R7; wherein R1 may be optionally substituted on the carbon with one or more R8; and wherein if the heterocyclic group contains a -ΝΉ- moiety, then Nitrogen may be optionally substituted with a group selected from R9; R7 is selected from -C(O)-, -C(0)N(R15)., -s(0)2- or -S02N(R16)-; R15 and R1 6 are hydrogen; R8 is selected from the group consisting of halo, nitro, hydroxy, amine, Cl-6 alkyl, Cl 6 alkoxy, N-(Ch alkyl)amine, hydrazine, hydrazine ((ν6 alkane) Or an amino group, a carbocyclyl-Ri7_ or a heterocyclic group-R18-; wherein R8 may be optionally substituted on the carbon with one or more Ri9; and wherein if the heterocyclic group contains a -Ml. moiety, The nitrogen may optionally be substituted with a group selected from R 2 G; the R 9 and R 2 G systems are independently selected from the group consisting of C -6 alkyl, C V 6 alkyl fluorenyl, C V 6 alkoxycarbonyl and benzyloxycarbonyl; wherein R 9 and R 2 G may be Independently, as appropriate, substituted on the carbon by one or more R21; 120858 - 21 - 200811169 R17 and R18 are independently selected from direct linkage or _N(R22)_; wherein R22 is selected from hydrazine or CV6 alkyl; And R19 and R21 are independently selected from the group consisting of a halogen group, a cyano group, a hydroxyl group, an aminomethyl group, a methyl group, a propyl group, a cyclopropyl group and a methoxy group. R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen and A. Base, ethyl, propyl, isopropyl, ethenyl, propyl fluorenyl, butyl sulfonyl, sulfonyl, methoxycarbonyl, ethoxylated, tert-butoxycarbonyl, methanesulfonyl, ethyl Sulfosyl, propylsulfonyl, vinylsulfonyl or hexahydropyridyl-R7; wherein R1 may be optionally substituted on the carbon with one or more R8; wherein R7 is -C(O)-; R8 Selected from gas group, hydroxyl group, mercapto group, methoxy group, ethylamino group, isopropylamino group, propylamino group, butan-2-ylamino group, third-butylamino group, 3-methylbutylamine , phenyl-R17-, hexahydropyrryl, Ri8, hexahydropyridyl-Ris-, morpholine-R1 or tetrahydropyrrolyl-Ri8·; wherein R8 may be one or Substituting a plurality of R19; and wherein the hexahydropyridyl or hexahydro The cultivating base may optionally be substituted on the nitrogen by a group selected from R 2 fluorene; R 20 is selected from a mercapto group, an ethyl group or a tert-butoxycarbonyl group; wherein R 2 〇 may be optionally substituted on the carbon by one or more R 2 1 R17 and R18 are direct bonds; and R19 and R21 are independently selected from a hydroxyl group and a methoxy group. R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, Ethyl, propyl, butyl, aminomethyl, N-methylamine, N-ethylamine, N,N-dimethylamine, sulfonyl, N-ethylamine sulfonyl, N-propylamine sulfonyl, N-(2,2-dimethylpropyl)amine 碏120858 -22- 200811169 fluorenyl, N-methyl-N-propyl Amine, N,N-dimethylamine, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, ethylsulfonyl, propyl sulfhydryl, 3-methylbutylsulfonyl, vinylsulfonyl, morpholinyl-R7, homohexahydropyrryl-R7, hexahydropyrryl-R7, tetrahydropyrrolyl-R7 or hexahydropyridine a group -R7; wherein R1 may be substituted on the carbon by one or more R8, and wherein the konofolin, The hexahydroindole p-based, hexahydro-p-pyryl, hexahydroindenyl or tetrahydropyrrole may be optionally substituted with a group selected from R9; R7 is selected from -C(O)-, -C (0) N(R15)-, -S(0)2_4-S02N(R16)-; wherein R15 and R1 6 are hydrogen; R8 is selected from the group consisting of a gas group 'nitro group, a mercapto group, an amine group, a fluorenyl group, and a group Oxyl, methylamino, N-ethylamino, N-propylamino, N-isopropylamino, N-butyl-2-amino, 3-mercaptobutyl-2-ylamino, 2 _Methylpropylamino, hydrazine, hydrazine-diamine, hydrazine, hydrazine-diethylamino, hydrazine-methylethylamino, hydrazine-methyl-N-isopropylamino, cyclopentyl -R17-, cyclobutyl-Ri, cyclopropyl-Ri7_, phenyl-Ri7... whallotyl-R1 8 _, homomorpholinyl _Ri8 -, thiotropolinyl _Ri8 — High thiomorpholinyl-R18-, hexahydropyridyl_Ri8 _, 'azabicyclo[2.21]heptyl-R18_, 2-azabicyclo[2.2.2]octyl-Ri, 6-azbicyclo And [2·2.2] octyl-R18·, nitrotetradecyl-Ri8_, tetrahydropyrrolyl-Rl8_, ketohexahydropyrrole-R18_, 2-keto-based hexahydropyrrolyl _Ri 8_ , high hexahydropyridinyl-Ri 8_ or hexahydropyrrole-R1 8 -; wherein R8 may be Or a plurality of r1 9 substituted; and wherein the high hexahydropyridinyl, tetrahydropyrrolyl, hexahydropyrrole or hexahydroacridinyl is optionally substituted on the nitrogen with a group selected from R 2 fluorene; R 9 and R2 is independently selected from the group consisting of decyl, ethyl, isopropyl, ethenyl, tert-butoxycarboxy and benzyloxycarbonyl; wherein R9 and R2 are independently of each other depending on the situation 120858 -23 · 200811169 on carbon Substituted by one or more R 2 1 ; R and R 18 are independently selected from the direct bond 4_N(R22)_; wherein R22 is selected from hydrogen or methyl; and R19 and R21 are independently selected from thiol, cyano, hydroxy , amidino, methyl, propyl, cyclopropyl and methoxy. R1 is a substituent on nitrogen and is selected from the group consisting of hydrogen, methyl, propyl, isopropyl, vinyllithic acid, decanesulfonyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethyl , phenethyl, ethoxycarbonyl, 2-methoxyethyl, sulfonyl, aryl, 3-cyclopropylsulfonyl, 3-(2-methoxyethyl) propyl sulfonate , 3-propylsulfonyl, 3-(1-hydroxypropionyl)propylsulfonyl, 3-(1-methylhexahydroindole) propylsulfonyl, hydroxyethyl )) hexahydropyranyl] propyl decyl, 3-tetrahydropyrrolidinyl sulfonyl, 3-formoloxypropylsulfonyl, 3-(1-hydroxybut-2-) Aminosulfonyl)propylsulfonyl, 3-(1-methoxypropan-2-ylamino)propylsulfonyl, 3-(2-hydroxypropylamino)propylsulfonyl, 3_ (1-hydroxy-3-methylbutyrylamino)propylsulfonyl, 4-morpholinylbutanyl, 3-(1-mercaptomethylpropan-2-ylamino)propylsulfonyl , 3-(hexa-pyridyl-4-yl)propanyl, 2-(1-methylhexahydropyrryl-4-yl)ethylsulfonyl, 2-tetrahydropyrroleylethylsulfonate Base, 2-(2-methoxyethylamino)ethylsulfonyl, 2_(]μ Third-butoxy-ylhexahydropyridin-4-yl)ethenyl, 3-(1-tris-butoxycarbonylhexahydropyrryl-4-yl)propanyl, 2-(hexahydropyridine-4 -yl)ethinyl, 3-(1-tris-butoxycarbonylhexamethylene p-buty-4-yl)propionic acid group, 2-(1-third-butoxyhexylhexahydro-p ratio σ 3-yl)ethenyl, 1·t-butoxycarbonyl-4-methylhexahydropyridylcarbonyl, 3·(hexahydropyridin-4-yl)propanyl, 4-methyl-6 Hydropyridin-4-ylcarbonyl and 2-(hexahydropyridin-3-yl)ethenyl. 120858 -24- 200811169 R1 is a substituent on nitrogen and is selected from the group consisting of hydrogen, methyl, propyl, isopropyl, vinylsulfonyl, decanesulfonyl, fluorenylcarbonyl, and third-butoxy Carbonyl, ethyl hydrazino, phenethyl, ethoxycarbonyl, 2-methoxyethyl, sulfonyl, N,N-dimethylamine sulfonyl, ν, ν-dimethylaminocarbamyl , benzyl, amine methyl sulfhydryl, N-methylamine methyl sulfhydryl, 2-(diguanyl) ethyl sulfonyl, 2-(N•methyl | isopropyl) ethyl fluorenyl, 2- (1-methylhexahydroexo-4-yl)ethylsulfonyl, 2-tetrahydropyrroleylethylsulfonyl, 2-(3·fluorotetrahydropyrrole-1-yl)ethylsulfonate Sulfhydryl, 2-(thiomorpholin-4-yl)ethylsulfonyl, 2-(4-mercaptohexahydropyridin-1-yl)ethyl thiol, 2-(high hexahydrop乙-1-yl)ethyl methic acid, 2-diethylaminoethylsulfonyl, 2-nitrotetradec-1-ylethyl fluorenyl, 2-folfyl ethyl sulfonate Sulfhydryl, 2-(4-fluorohexahydropyridyl) ethylsulfonyl, 2-(4-cyanohexahydro-I:di-1-yl)ethyl thiol, 2-(4 -propylhexahydrop-p-quinone-based)ethyl thiol, 2-(4-aminocarbazinyl) Hydropyridine small) ethyl sulfonyl, 2-(7-azabicyclo[2·2·1]hept-7-yl)ethylsulfonyl, 2-(2-azabicyclo[2.2.2辛-2·yl)ethylsulfonyl, 2-(6•azabicyclo[2.2.2]oct-6-yl)ethylsulfonyl, 2-homomorpholinylethylsulfonyl , 2-(2-ketohexahydropyrrolidyl) ethylsulfonyl, 2-(1-ethylindenylhexahydropyrrolidin-4-yl)ethylglycosyl, 2-(2-methoxy Ethylamino)ethylsulfonyl, 2-(N-methyl-N-cyclopropyl)ethylsulfonyl, 2-(2-keto-hexahydropyridin-4-yl)ethylsulfonate Sulfhydryl, 2-(1-ethylindolylhexahydropyridin-4-yl)ethylsulfonyl, 2-(N-fluorenyl-N-cyclopropylmethyl)ethylsulfonyl, 2_ (High thiophenofin _4_yl) Ethyl sulfonyl, 3-chloropropyl sulfonyl, 3-dimethylaminopropyl sulfonyl, 3-dimethylamino-2, 2 - dimethylpropylsulfonyl, 3-diethylaminopropylsulfonyl, 3-(2-methoxyethylamino)propylsulfonyl, 3-[N-methyl-N- (2-methoxyethyl)amino]propyl propyl, 3·propyl propyl, 3-(1-propan-2-ylamino)propyl 120858 -25- 200811169 ～Si&amp ; base, 3-(1-methyl Hydrogen pyridin-4-yl)propyl thiol, 3-(1-isopropylhexahydropyrylene-4-yl)propylsulfonyl, 3-(6-azabicyclo[2 2 2]octyl _6-yl) propyl stone male base, 3-(7-azabicyclo[2·2·1]g-7-yl)propylsulfonyl, 3-[i-(2-ethyl) Hydroquinone-4-yl]propylsulfonyl, 3_tetrahydropyrrole_ι-propylsulfonyl, 3 (1'4 monomethyltetralyl) propyl thiol, 3-fosfosylpropyl fluorescein, 3-(1-hydroxybutan-2-yl)propylsulfonyl, 3-(1-methoxypropan-2-yl)propylsulfonyl, 3-(2-hydroxypropylamino)propylsulfonyl, ^(1)hydroxy-3-indolyl-2-ylamino)propylsulfonyl, 3-(1-carbo-2-yl Propionyl-2-ylamino)propylsulfonyl, 3-(hexahydropyridyl)propylsulfonyl, 3-(cyclopropylamino)propyl, 3-(N-methyl -N-cyclopropylamino)propylsulfonyl, 3-(cyclopentylamino)propylsulfonyl, 3-(N-methylcyclopentylamino)propylsulfonyl, anthracene Aminomethyl)propyl hydrazino, 3-(N-fluorenyl-N-cyclobutylamino)propyl fluorenyl, 3-(isopropylamino)propylsulfonyl, 3-(N-A --N-isopropylamino) propyl κ, 3-(N-fluorenyl-N-ethylamino)propyl fluorenyl, 3-[N-methyl-N-(2_cyano) Amino]propylsulfonyl, 3-[N-ethyl-N-(2-cyanoethyl)amino]propyl-based, 3-cyclotetradec-1-ylpropyl Yellow-branched, 3-(cyclopropylmethylamino)propylsulfonyl, 3-(N-fluorenyl-N-cyclopropylmethylamino)propylsulfonyl, 3-nitro-3- Butyl butyl ketone, 3-amino-3-methylbutyl fluorenyl, 3-dimercapto•3·methylbutyl fluorenyl, 2-(hexahydrofolate b _3_yl) ethenyl , 2-(1-tert-butoxycarbonylhexahydropyridin-3-yl)ethenyl, 2-(hexahydropyridin-4-yl)ethenyl, 2-(1-tri-butoxycarbonyl) Hexahydropyridyl yl) acetyl, 2-dimethylaminoethyl, 3-(1-tris-butoxycarbonylhexahydropyridin-4-yl)propanyl, 3-(1- Tri-butoxy-weiylhexahydro-p-buty-4-yl)propanyl, 3-(hexahydrop-buty-4-yl)propanyl, 3-(hexahydropyridin-4-yl)propane Sulfhydryl, 3-dimethylaminopropyl fluorenyl, 4 phoryl p-linyl, 4-120858 -26- 200811169 dimethylaminobutanyl, ι_tri-butoxycarbonyl chlorohydrazine Bisylcarbylcarbonyl, 4-methylhexahydrogenate 1: bite _4. carbonyl, μ, third, butoxycarbonyl, methylhexahydropyridine, carbonyl, 4-methyl, hexahydropyridinyl carbonyl , μmethylhexahydropyridin-3-ylcarbonyl, 1-methyltetrahydropyrrolidinocarbonyl, 3-dimethylaminotetrahydropyrrol-1-yl, 4-tert-butoxycarbonyl吗福 _2 _2 _ _ 羰 吗 吗 吗 吗 吗 1- 1- 1- 1- 1- 1- 1- 1- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( Aminomethyl hydrazino, fluorenyl-(2-tetrahydrofurfurylethyl)amine methyl sulfonyl, ν_(2-monomethylaminoethyl)amine carbaryl 'N-(l-methylhexahydro ρ ratio唆冰基)amine sulphate, N-(l-isopropylhexahydro ρ than sigma-4-yl)amine sulphate, 2-(dimethylamino)ethylamine sulfonate, 2-(2-B Amino)ethylamine sulfonyl, 2-(moffipyl)ethylamine sulphate, 2-(1-methylhexahydropyranyl)ethylamine sulfonyl, 2-( 1-methyltetrahydropyrrole 1-yl)ethylamine sulfonyl, 3-(tetrahydropyrrole-yl)propylaminesulfonyl, 3-(3-fluorotetrahydropyrroleyl)propyl Aminesulfonyl, 3-diaminoamine-2,2·monomethylpropyl Sulfosyl, 3-(hexahydropyridin-1-yl)propylamine sulfonyl, N-methyl 1(3-dimethylaminopropyl)amine sulfonyl, 3-dimethylaminotetrahydro Pyrrole-based sill-based base, i-methylhexahydropyrrol-4-ylsulfonyl, 1-methylhexahydropyridine_4_ sulphate, μ-isopropylhexahydropyridin-4-ylsulfonate Base and μmethyl high hexahydropyridin 11 well _4_ sulfonyl sulfhydryl. q is 0 〇 R3 is _ base. R is a murine or gas base. η is 〇 〇 η is 1 〇 η is 0 or 1. 120858 -27- 200811169 R4 is isopropyl. R4 is a cyclopentyl group. R4 is selected from isopropyl or cyclopentyl. R5 is a methyl group. 5 clothes A, Ri, R2 and q form a 1-butanyl-4-hexazone^ sigma group, 1-ethyl aryl tetrahydro outside b σ -3-yl, 1-benzyl-4- Hexahydro outside b-bite, 1-benzyloxymethyl-4-hexahydroacridinyl, 1-aminomethylindol-4-hexahydropyridyl, 1-ethoxycarbonyl-4-hexahydropyridyl, 1-isopropyl-4-hexahydropyridyl, 1-methyl-4-hexahydropyridyl, 1-methylsulfonyl-4-hexahydroindole, 1-methylglycosyltetrahydro-u-bi 3-yl, 1-phenylethyl-4-hexahydropyridinium sigma, 1-propyl-4-hexanitro-p-indenyl group, 1-amine-based S-sulphonyl-4-hexachloro-p-sigma , 1-amine sulfonyltetrahydropyrrol-3-yl, 1-tris-butoxycarbonyl-4-hexahydropyridyl, 1-tris-butoxycarbonyltetrahydropyrrole-3, 1-vinyl Sulfosyl-4-pyridinyl, (lR,5S)-3-(2-dimethylaminoethylsulfonyl)-3-azabicyclo[3.1.0]hex-6-yl, (lR,5S)-3-(2-tetrahydropyrrol-1-ylethylsulfonyl)-3-azabicyclo[3丄〇]hex-6-yl, (lR,5S)-3-( 3-dimethylaminopropylsulfonyl)-3-azabicyclo[3丄〇]hex-6-yl, (lR,5S)-3_(3·tetranitropyrrolidino-1-propylpropyl ——(7) lR,5S)-3-[2-(7.azabicyclo[2.2.1]hept-7-yl)ethylsulfonyl]soxabicyclo[3.1.0]hex-6-yl, (lR ,5S)-3-[3-(l-hexahydropyridyl)propylsulfonyl]-3-azabicyclo[3.1_0]hex-6-yl, (lR,5S)-3-[3- (2,5-Dimethyltetrahydropyrrol-1-yl)propylsulfonyl]-3-azabicyclo[3丄0]hex-6-yl, (lRjSp-Ka-azabicyclo[2· 2·1]hept-7-yl)propylsulfonyl]-3-azabicyclo[3.1.0]hexyl, (lR,5S)-3-[3-(cyclopentyl)indolyl- Amino)propylsulfonyl]_3·azabicyclo[3·1·〇]hex-6-yl, (lR,5S)-3-azabicyclo[3.1.0]hex-6-yl, lR,5S)-3-aryloxycarbonyl-3_azabicyclo[3·1·0]hex-6-yl, (lR,5S)-3-methanesulfonyl-3-nitrobicyclo and 120858 -28 - 200811169 [3·1·0]hexyl, (1R, 5S) methyl-8-azabicyclo[3.2.1]oct-3-yl, (3R)-1-methylsulfonyl-3 - hexahydropyridyl, (3R) small tris-butoxycarbonyl-3-hexahydropyridyl, (3R)-3-hexahydrop butyl, (3S)-1-methyl fluorenyl-3-6 Hydrogen outside 1: bite group, (3S)-1-tris-butoxycarbonyl-3-hexahydropyridyl, (3S)-3-hexahydropyridyl, 1-(1-methyl Six mouse p than biting-3-weiki)-4-hexaquinone p than sigma, 1-(1-methyltetrazolium p than slightly-2-yl)-4-hexanitro? Ratio of sigma-based, diethylaminoethylamine yellow wine to 4-hexanitro-p. Stationary, 1-(2-diethylaminoethyl S-base)-4-hexahydro-exclusive b σ-based, 1-(2-dimethylaminoethenyl)-4-hexahydropyridyl, 1 -(2-dimethylaminoethylaminecarbamyl)>4-hexahydropyridyl, 1-(2-dimethylaminoethylaminemethane)tetrahydropyrrol-3-yl, 1-( 2-dimethylaminoethylamine phosphatyl)-4-hexanitro-p-indenyl, 1-(2-dimethylaminoethyl phosanthin)-4-hexanitrogen sigma, 1- (2-methoxyethyl)-4-hexa-pyrene ratio σ-based, 1-(2- whuf-ethylidene ethylamine sulphate)-4-hexanitro-p-butyl, 1-(2-吗福ρ-Linylethylsulfonyl)-4-hexahydropyridyl, 1-(2-tetrahydropyrrol-1-ylethylaminemethyl fluorenyl)-4-hexanitro-p-indenyl, 1- (2-four mouse outer b-l-yl-ethylethylamine sulphate)-4-hexanitro-p-r σ-based, 1-(2-tetrazo ρ-ha-1-ylethyl) -4-6 rats said sigma, 1-(2-thiophene p-l-ethylethyl tartrage)-4-hexanitro-p-bityl, 1-(3-amino-3-indolyl- Butyl) sulphate-4 hexahydrofolate 1: sigma, 1-(3-chloropropyl sulphate)-4_hexahydrop to π-based, 1-(3-a propylpropyl sulfhydryl) Tetrahydropyrrol-3-yl, 1-(3-di Ethyl propyl sulfonyl)-4-hexahydropyridinyl, 1-(3-dimethylamino-3-methyl-butyl) fluorenyl-4 hexahydropyridinyl, 1-(3- Dimethylaminopropenyl)-4-hexahydropyridyl, 1-(3-dimethylaminopropyl-methyl-amine sulfonyl)-4-hexahydropyridyl, 1-(3-di Methylaminopropyl sulphate)-4-hexahydro]17-decidence, 1-(3-propyl sulphate)-4-hexahydrop-bite, 1-(3-methyl·3-nitro-butyl Base) 醯 醯 hexahydropyridyl, H3-morpholinopropylsulfonyl)-4-hexahydropyridyl, 1-(3·hexahydropyrrolidinyl)-4·6 Hydrogen 120858 -29- 200811169 Exodentyl, 1-(3-hexahydroexo-1-ylpropenyl)tetrahydroindol-3-yl, 1-(3-tetrahydropyrrolidinylpropylsulfonate Mercapto)-4-hexahydropyridyl, 1-(3-tetrahydrop-pyrrolidylpropylsulfonyl)-4-hexahydropyridyl, 1-(3-tetrahydropyrrolidinyl sulfonate醯基) Four mouse p biro-3-yl, 1-(4-dimethylaminobutyryl)-4-hexanitrogen p sigma, i-(4_methyl-1,4-diaza sulphate Alkyl carbonyl)-4-hexahydropyridyl, 1-(4-methyl-small-butoxycarbonyl-hexahydropyridin-4-carbonyl) glahydropyridinyl, 1-(4 -Methyl small third-butoxycarbonyl-hexahydropyridine carbonyl)tetrahydropyrrol-3-yl, 1-(4-methylhexahydropy-1-yl)sulfonyl-4-hexahydrogen t» σ-based, 1-(4-methylhexahydro-b°--4-yl)-4-hexahydropyridyl, 1-(4-methylhexahydropyridine-4.carbonyl)tetrahydropyrrole Each group, 1-(4-morpholinylbutanyl)-4-hexahydropyridyl, 1-(4-hexahydropyridylsulfonyl)-4-hexaazide ratio sigma, 1_(4_ The third-butyl woven base whiffin-2-woven base) -4- six p-bite base, 1 (dimethylaminomethane)-4-hexahydropyridyl, 1- (dimethyl Thiamine sulfonyl)-4-hexahydrofolate 1: bite group, 1-(methylamine-mercapto)-4-hexahydrop-pyrylate, 1-(methylamine-mercapto)tetrahydropyrrole 3-yl, 1-(morpholine-2-carbonyl>4-hexahydropyridinyl, 1-[(1-methoxycarbonyl; hexahydropyridyl)methylsulfonyl] hexahydropyridyl, 1-[(1_benzyloxycarbonyl-4-hexahydropyridinyl)-inosinyl]-4-hexahydropyridinyl, μ[(1-isopropyl-4-hexahydropyridinyl)aminesulfonylhexahydropyridine Base, 1-[(1-isopropyl-4-hexahydroport to sigma) sulphate]-4_hexahydrofolate 1: sigma, 1-[(1-methyl-4-hexahydrop ratio Base Aminomethyl hydrazide] ice hexahydro hydrazine bite, 1-[(1_methyl-4-hexahydro ρ than octyl) amine fluorenyl]-4-hexahydroindenyl, 1-[(1- Methyl-winter hexahydro outside b ϋ ) ) 石 ] ] ] -4- -4- hexahydro ρ than bite, 1-[(3-dimethylamino-2,2-dimethyl-propyl) amine stone yellow Base]-4-hexachloro-p ratio. Stationary, 1-[(3R)_3-dimethylaminotetrahydropyrrol-1-yl]sulfonyl-4-hexahydropyridyl, l-[(3S)-3-dimethylaminotetrahydropyrrole- 1-carbonyl]-4-hexahydropyridinyl, 1-[(4.methyl-1,4-diaza heptadecane small) fluorenyl H-hexahydropyridyl, 1-[[(2R) small Ethyl tetra 120858 -30- 200811169 Hydropyrrol-2-yl]methylamine fluorenyl] ice hexahydropyridyl, oxime, ethyltetrahydropyridin-2-yl]methylamine thiol冰 氲 氲 pyridyl, 1-[2_(1,4-oxazin-7-yl)ethylsulfonyl] hexahydropyridyl, ^[2-(1,4-thiazolidine-7)圜冰基)ethylsulfonyl]-4_hexahydropyridyl, μρχμmethyltetrahydropyrrole_2-yl)ethylaminesulfonyl]-4-hexahydropyridyl, hexahydropyridyl) Alkyl sulfhydryl] ice hexahydropyridyl, 1-[2-(1-tris-butoxycarbonyl) hexahydropyridinyl) hexylhydrogenate 1: sigma, 1-[2-(1 -Third-butoxy-Wiki-4-hexahydrobatchyl)Ethylthiol]tetrahydropyrrol-3-yl, 1-[2-(2-decyloxyethylamino)ethylsulfonyl] _4_hexahydropyridyl, 1Κ3-ketohexahydropyrazine small base) ethyl sulphate] hexahydropyrrolidine, 1 Κ 4-ethyl aryl-1, 4-nitrogen sulphide small base) ethyl sulphate base]_4_hexahydro ρ ratio sigma, 1-[2-(4-ethenylhexahydropyrrolidine)ethylsulfonyl group> 4-hexahydropyridyl, 1-[2-(4-aminomethylindolyl-1-hexahydropyridinyl)ethylsulfonyl]- 4-hexahydropyridyl, 1-[2-(4-cyano) -1·hexa-pyridyl)ethylsulfonyl]_4_hexahydropyridyl, i-[2-(4-fluoro-1-pyropyridinyl)ethylsulfonyl]-tetrahydropyridine Base, 1-[2-(4-methyl small hexahydro outside 1: σ-decyl) ethyl sulphate]-4·hexahydro ρ ratio π-based, ΐ-[2-(4-methylhexahydropterin ρ Well-1-yl)ethylamine-based base]-4-hexahydroindole σ-based, ΐ-[2-(4-mercapto- 6-membered external cultivating _1_yl) ethyl sulfonyl]-4 - hexahydropyridyl, 1-[2-(4-hexahydropyridinyl)ethenyl] hexachlorocyclohexane, 1-[2-(4-hexahydrop-bite) Hydrogen p-bi-3-yl, 1-[2-(4-propyl-1-hexahydropyridyl)ethylsulfonyl]-4-hexahydropyridyl, 1-[2-(5-oxygen) Keto, keto-1,4-diaza heptadec-1-yl)ethylsulfonyl] ice hexahydropyridyl, 1-[2-(7-azabicyclo[2·2·1]g ·7-yl)ethylsulfonyl]-4-hexahydropyridyl, 1-[2-(8-nitrogen) Cyclo[2·2·2]oct-8-yl)ethyl hydrazino]-4-hexahydrobatch sigma, 1-[2-(-aza-tetradec-1-yl)ethylsulfonyl ]-4-hexahydropyridyl, 1-[2-(cyclopropyl-methyl-amino)ethylsulfonylhydrazine·hexahydropyridyl, 1-[2-(cyclopropylmethyl-methyl 120858) -31 - 200811169 benzyl-amino) ethyl fluorenyl]-4-hexahydroP to π-based, 1_[2_(isopropyl-methyl-amino)ethyl hydrazino] hexahydroacridine Third, _butoxycarbonyl, hexahydro outside, fluorenyl]acetate, hexahydropyridyl, i_[2-[(3R), small, third-butoxycarbonyl-3-hexahydroindole Ethyl hydrazide] tetrahydropyrrole _3_yl, fluorotetrahydroisoindolo-1-yl]ethylsulfonyl]-4-hexahydropyridyl, each hexahydropyridyl]ethinyl]- 4-Hexidopyridinyl, H2-[(3R)_3_hexahydropyridinyl]ethenyl]tetrahydropyrrol-3-yl, 1-[2-[(3S) small third-butoxycarbonyl_3 _ hexahydropyridyl]ethyl hydrazide] hexahydropyr p-pyridyl, 1-[2-[(3S)_l-tris-butoxycarbonyl_3_hexahydropyridyl]ethinyl]tetrahydropyrrole 3-yl, l_[2-[(3S)-3-fluorotetrahydropyrroleyl]ethylsulfonyl]-4-hexahydrofolate b π-decyl, i_[2-[(3S)-3 - hexahydrop to bite base] ethyl thiol]_ Hexahydropyridyl, 1-[2-[(3S)-3-hexahydropyridyl]ethenyl]tetrahydropyrrole-3-yl, 1-[3-(1-hexahydropyridyl)propylamine Sulfhydryl]_4_hexahydropyridyl, hexahydropyridyl)propyl fluorenyl] ice hexahydropyridyl, 1-[3-(1_third-butoxycarbonyl-4-hexahydro outside b bit Propionyl]-4-hexahydrop ratio sigma, third-butoxymethyl_4_hexahydropyridyl)propanyl]tetrahydropyrrol-3-yl, 1-[3-(2- Cyanoethyl-ethyl-amino)propylmercapto]-4-hexahydropyridyl, 1-[3-(2-cyanoethyl-methyl-amino)propyl thiol ]-4-hexahydroρ ratio bite group, 1-[3-(2-propylamino)propyl tartaric acid]-4-hexahydropyridyl, 1-[3-(2-methoxyl) Ethylamino)propylsulfonyl]_4_hexahydropyrene sigma, 1-[3-(2-methoxyethylamino)propyldinyl]tetrahydropyrrol-3-yl, 1-[3-(2-methoxyethyl-methyl-amino)propyl-based]hexa-nitro-p ratio t?-defined, 1-[3-(4-isopropylhexa-6-p-p ratio p井小基) propyl fiber base] four nitrogen p than 洛_3_ base, Bu [3- (4-methylhexahydropyrazine small base) propyl sulfonyl] _4_ hexahydropyridyl, i -[3-(4-methylhexahydropyrrolidin-1-yl)propylsulfonyl] Hydropyrrole _3_yl, l-[3-(4-hexahydroport σ stil) propyl fluorenyl]-4-hexahydroP thiol, 1-[3-(4_hexahydroquinonecr) Propyl fluorenyl] 120858 -32- 200811169 Tetrahydropyrrolidyl, H3-(4-Tertiary-butoxycarbonylhexahydropyrazine·丨_yl)propanyl]Isole hexahydropyridyl, ^[3-( 44 tris-butoxycarbonylhexafluoropyrazine small base) propyl fluorenyl] tetrahydroinozol-3-yl, 1-[3-(7-azabicyclo[2.2.1]hept-7-yl)propyl Sulfhydryl H·hexahydropyridyl, 1-[3-azabicyclo[2 2·2]octyl)propylsulfonyl]-4-hexahydropyridyl, mononitrotetradecyl)propyl Sulfosyl] winter hexahydropyridyl 11-yl ' 1-[3-(cyclobutylamino)propylsulfonic acid]_4_hexahydro sigma, cyclobutyl-methyl-amino) propyl Sulfosyl]_4_hexahydropyridyl, (cyclopentylamino)propylsulfonylhydrazine-hexahydropyridyl, 丨#·(cyclopentyl-methyl-amino)propylsulfonyl ] hexahydropyridyl, H3_(cyclopropylamino)propylsulfonyl]_4_hexahydropyridyl, 1-[3_(cyclopropylguanidino)propylsulfonyl]_4_hexahydropyridine , [[3-(cyclopropyl-methyl-amino)propylsulfonyl] ice hexahydropyridyl, (cyclopropylmethyl-methyl) -amino)propylsulfonyl]ice hexahydropyridyl, 丨[[3_(ethyl-methyl-amino)propylsulfonyl]-4_hexahydropyridyl, μ[3_(isopropyl Amino)propyl propyl hexahydropyridyl, μρ-(isopropyl-methyl-amino)propylsulfonyl>4-hexahydropyridyl, hydroxydimethyl-B Amino]propylsulfonyl]+hexahydropyridyl 'H3-[(2-hydroxysuccinyl-ethyl)amino]propylsulfonylhexahydropyridyl, H3-[(2- Methoxy-1-methyl-ethyl)amino]propylsulfonyl] ice hexahydropyridinyl, H3-[(3S)-3-fluorotetrahydropyrroleyl]propylamine sulfonyl M-hexahydropyridyl, HH[1-(hydroxymethyl)-2-methyl-propyl]amino]propylsulfonyl]-4-hexahydropyridyl, H; H1_(hydroxymethyl)propylamine Propylsulfonyl]-4-hexachloropurine sigma, 1-[3-[冬(2•hydroxyethyl)hexahydropyrazine)]propylsulfonyl>4-hexahydropyridine a group, a 4_hexahydropyridyl group, a hexanitrodecane-3-yl group, a tetrahydrogen port ratio of each -3-yl group, and a 1-(third-butoxycarbonyl)-aza heptadecane_3_ group. Accordingly, in a further aspect of the invention there is provided a compound of formula (I) (as depicted in the above-mentioned 120858-33-200811169), wherein: ring A is a 5 or 6 membered saturated heterocyclic ring containing a nitrogen atom; wherein ring a The two atoms may be connected by a bridging group as the case may be; R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, Ci4 alkyl, alkyl fluorenyl, amine tartaric acid, Cl_6 alkoxy group, and Ch-based a radical, a dilute or a heterocyclyl-R7; wherein Ri may be substituted on the carbon by one or more hydrazines; q is 0; η is hydrazine; R4 is isopropyl; R5 is methyl; R7 is -C(o)-; R8 is selected from the group consisting of a hydroxy group, a hydroxy group, a C 6 alkyl group, a Ci 6 alkoxy group, an n-(Ch alkyl) group, a cyclyl-R' or a heterocyclic group pR8, optionally in the form of carbon. Substituted by R19; and wherein if the heterocyclic group contains a cleavage moiety, the nitrogen may be optionally substituted with a group selected from R2? R is selected from c1-6 alkyl or c1- 0 alkoxycarbonyl; wherein R 2 〇 may be substituted on the stone by one or more R 2 1;

Rl 7與R18為直接鍵結；且 R與R21係獨立選自羥基與甲氧基； 或/、某學上可接受之鹽或活體内可水解酯。 因此於本發明之進一步方面，係提供式⑴化合物（如上 文所描緣）’其中：Rl 7 and R18 are direct bonds; and R and R21 are independently selected from hydroxy and methoxy; or /, a stoichiometric salt or in vivo hydrolysable ester. Thus in a further aspect of the invention, there is provided a compound of formula (1) (as described above) wherein:

%八為5或6員飽和雜環，其含有一個氮原子；其中環A 120858 -34- 200811169 之2個原子可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Ci-6烷基、Ci_6烷醯基、 胺甲醯基、Ν-θυ烷基）胺甲醯基、N，N-(Ch烷基）胺甲醯基、 胺磺醯基、Ν-((^ _6烷基）胺磺醯基、ν,ΝΚΑ _ 6烷基)2胺磺醯基、 Cl·6烧氧魏基、Cn烧基磺醢基、Ci-6浠基績醯基或雜環基 -R7 ;其中R1可視情況在碳上被一或多個R8取代；且其中若 该雜環基含有部份基團，則該氮可視情況被選自r9之 基團取代； q為0 ; R3為i基； η為0或1 ; R4係選自異丙基或環戊基； R5為甲基； R7係選自-C(O)-、-C(0)N(R15)-、-S(0)2-或-S02N(R16)-;其中 R15與R16為氫； R8係選自鹵基、硝基、羥基、胺基、烷基、Cle6烷氧 基、N-A·6烷基）胺基、n，N-(Ch烷基）2胺基、碳環基也久 或雜環基-R18 -;其中R8可視情況在碳上被一或多個Rl 9取 代，且其中若该雜環基含有-NH-部份基團，則該氮可視情 況被選自R2 G之基團取代； R9與R2G係獨立選自Cl·6烷基、Cl-0烷醯基、Cl·6烷氧羰基 及苄氧羰基；其中R9與r2〇可互相獨立地視情況在碳上被一 或多個R21取代； R17與R18係獨立選自直接鍵結4_N(R22>;其中R22係選自 120858 -35- 200811169 氫或烷基；且 R19與R21係獨立選自鹵基、氰基、羥基、胺甲醯基、甲 基、丙基、環丙基及甲氧基； 或其藥學上可接受之鹽或活體内可水解酯。 因此，於本發明之進一步方面，係提供式①化合物（如上 文所描繪），其中： 環A為（1 α，5 α，6 a )-3-氮雙環并P.1.0]己烷-3-基、（R)-六氫吡 啶-3-基、（S)-六氫吡啶各基、六氫吡咬_4_基、四氫吡咯-3-基 或内向-8_氮雙環并[3.2.1]辛-3-基； R1為氮上之取代基，且係選自氫、甲基、丙基、異丙基、 乙烯基石黃醯基、曱烧績醯基、苄氧羰基、第三·丁氧羰基、 乙醯基、苯乙基、乙氧羰基、2-曱氧基乙基、胺磺醯基、 N，N_二甲基胺磺醯基、n，N-二曱基胺甲醯基、苄基、胺甲醯 基、N-甲基胺甲醯基、2-(二曱胺基）乙基磺醯基、2-(N-甲基-N-異丙基）乙基石黃醯基、2-(1-甲基六氫吡畊-4-基）乙基績醯基、 2-四虱峨洛-1-基乙基績醢基、2-(3·氟基四氳卩比u各小基）乙基石黃 醯基、2-(硫代嗎福啉_4·基）乙基磺醯基、2-(4-甲基六氫吡啶小 基）乙基磺醯基、2-(高六氫吡啶-1-基）乙基磺醯基、2_二乙胺 基乙基磺醯基、2-—氮四圜-1-基乙基磺醯基、2-嗎福啉基乙 基磺醯基、2-(4-氟基六氫吡啶-1-基）乙基續醯基、2-(4-氰基六 氫峨咬-1-基）乙基確醯基、2·(4·丙基六氫峨a定_1_基）乙基確醯 基、2-(4·胺甲醯基六氫吡啶-1-基）乙基磺醯基、2_(、氮雙環并 [2.2.1]庚-7-基）乙基磺醯基、2-(2-氮雙環并[2.2.2]辛-2-基）乙基磺 醯基、2-(6-氮雙環并[2.2.2]辛-6-基）乙基磺醯基、2_高嗎福啉基 120858 -36 - 200811169 乙基磺醯基、2-(2-酮基六氫吡畊-4-基）乙基磺醯基、2-(1-乙醯 基六氫吡畊冰基）乙基磺醯基、2-(2-甲氧基乙胺基）乙基磺醯 基、2-(N-甲基-N-環丙基）乙基磺醯基、2-(2-酮基高六氫吡_斗 基）乙基石買酿基、2-(1-乙酿基南六鼠p比啡-4-基）乙基石黃酿基、 2- (N-曱基環丙基甲基）乙基磺醯基、2-(高硫代嗎福啉-4-基） 乙基續酿基、3-氣基丙基績酿基、3-二甲胺基丙基石黃酿基、 3- 二甲胺基-2,2-二甲基丙基磺醯基、3-二乙胺基丙基磺醯 基、3-(2-甲氧基乙胺基）丙基石黃酿基、3-[N-甲基甲氧基 乙基）胺基]丙基石黃醯基、3-經丙基石黃醯基、3-(1-經丙-2-基胺 基）丙基磺醯基、3-(1-曱基六氫说_ -4-基）丙基績醯基、3-(1-異丙基六氫吡畊冰基）丙基磺醯基、3-(6-氮雙環并[2.2.2]辛-6-基）丙基磺醯基、3-(7-氮雙環并[2.2.1]庚-7-基）丙基磺醯基、 3-[1-(2-經乙基）六氫外b味·4_基]丙基績醢基、3-四氳外b p各-1-基丙 基石黃醯基、3-(1，4-二甲基四氫p比洛-1-基）丙基石黃酿基、3·嗎福 啉基丙基磺醯基、3-(1-羥基丁 -2-基胺基）丙基磺醯基、3-(1-曱氧基丙-2·基胺基）丙基磺醯基、3-(2-羥丙基胺基）丙基磺醯 基、3-(1-經基-3-甲基丁 -2-基胺基）丙基石黃醯基、3-(1-經基-2-甲基丙-2-基胺基）丙基績隨基、3-(六氫峨唆-1-基）丙基石黃醯 基、3-(環丙胺基）丙基磺醯基、3-(N-甲基-N-環丙胺基）丙基磺 醯基、3-(環戊基胺基）丙基磺醯基、3-(N-甲基環戊基胺基） 丙基磺醯基、3-(環丁基胺基）丙基磺醯基、3-(N-甲基-N-環丁 基胺基）丙基磺醯基、3-(異丙基胺基）丙基磺醯基、3-(N-甲基 -N-異丙基胺基）丙基磺醯基、3-(N-甲基乙胺基）丙基磺醯 基、3-[N-甲基-N-(2-氰基乙基）胺基]丙基石黃醯基、3-[N-乙基 120858 -37- 200811169 -N-(2-氰基乙基）胺基]丙基磺醯基、3-一氮四圜小基丙基磺醯 基 >(環丙基甲胺基）丙基石黃醯基、3-(N-甲基-N-環丙基甲胺 基）丙基石頁醯基、3_硝基-3-甲基丁基石黃醯基、3_胺基-3-甲基丁 基磺醯基、3-二甲基-3-曱基丁基磺醯基、2_(六氫吡啶各基） 乙醯基、2·(1-第三-丁氧羰基六氫吡啶_3_基）乙醯基、2-(六氫 口比唆-4-基）乙醯基、2-(1-第三-丁氧羰基六氫吡啶斗基）乙醯 基、2_二曱胺基乙醯基、3-(1_第三-丁氧羰基六氫吡畊冰基） 丙醯基、3_(1_第三-丁氧羰基六氫吡啶冰基）丙醯基、3_(六氫 外定-4-基）丙醯基、3-(六氫吡畊-4-基）丙醯基、3-二甲胺基丙 醯基、4-嗎福4基丁醯、4-二甲胺基丁醯基、μ第三-丁氧羰 基-4-曱基六氫吡啶斗基羰基、4·甲基六氫吡啶斗基羰基、1-弟二-丁氧幾基-4-曱基六氫说淀-4-基戴基、4-甲基高六氫p比 畊-1_基羰基、1-甲基六氫吡啶_3_基羰基、1_曱基四氫吡咯-2-基羰基、3-二甲胺基四氫吡咯-μ基羰基、4-第三-丁氧羰基嗎 福琳-2-基碳基、嗎福淋-2-基魏基、1-甲基六氫吨唆-4-基胺甲 醯基、Ν·(1_乙基四氫吡咯_2_基甲基）胺甲醯基、N-(2-四氫吡 咯-1-基乙基）胺甲醯基、N_(2-二甲胺基乙基）胺甲醯基、N-(l_ 甲基六氫吡啶_4_基）胺磺醯基、N-(l-異丙基六氫吡啶-4-基）胺 磺醯基、2-(二曱胺基）乙基胺磺醯基、2-(二乙胺基）乙基胺磺 醯基、2-(嗎福啉基）乙基胺磺醯基、2-(1-甲基六氫吡畊-4-基） 乙基胺績醯基、2-(1·甲基四氫吡咯-2-基）乙基胺石黃醯基、3-(四 氫外b 17各-1-基）丙基胺石黃醢基、3-(3-氟基四氫p比洛-1-基）丙基胺 磺醯基、3-二甲胺基-2,2-二曱基丙基胺磺醯基、3-(六氫吡啶 -1-基）丙基胺磺醯基、N-曱基-N-(3-二甲胺基丙基）胺磺醯基、 120858 -38 - 200811169 3-—甲胺基四氫吡咯+基磺醯基、丨_甲基六氫吡啡斗基磺醯 基、1-甲基六氫吡啶斗基磺醯基、；μ異丙基六氫吡啶斗基磺 醯基及甲基高六氫吡畊斗基磺醯基； q為0 ; R3為氟基或氯基； η為0或1 ; R4係選自異丙基或環戊基； R5為甲基； 或其藥學上可接受之鹽或活體内可水解酯。 因此，於本發明之進一步方面，係提供式①化合物（如上 文所描綠），其中： 裱八為5_7員飽和雜環，其含有一個氮原子；其中環八之之 個原子可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Ci 6烷基、6烷醯基、 胺甲醯基、Ν-((ν6烷基）胺甲醯基、n，n_(Ci-6烷基）胺甲醯基、 月女石頁醯基、Ν_((^ _6烷基）胺磺醯基、N，N_(Ci ·6烷基）2胺磺醯 基' A·6烷氧羰基、Ci-0烷基磺醯基、Ci 6烯基磺醯基或雜 環基-R7 ;其中Rl可視情況在碳上被一或多個R8取代；且其 中若4雜％基含有-nh_部份基團，則該氮可視情況被選自 R9之基團取代； q為0 ; R3為_基； η為0或1 ; R4係選自異丙基或環戊基； 120858 -39- 200811169 R5為曱基； R7係選自-C(O)-、、_s(0)2·或名〇2N(Rl6);其中 R15與R16為氫； R8係選自函基、硝基、羥基、胺基、Ci 6烷基、Ci 6烷氧 基、n_(Ch烷基）胺基、N，N-(C卜6烷基）2胺基、碳環基也乙 或雜環基-R18-;其中R8可視情況在碳上被一或多個Rl9取 代，且其中若該雜環基含有βΝΗ_部份基團，則該氮可視情 況被選自R20之基團取代； R與R係獨立選自Ch烧基、c卜6烧醯基、〇卜6烧氧羰基 及苄氧羰基；其中R9與r2g可互相獨立地視情況在碳上被一 或多個R21取代； R17與RU係獨立選自直接鍵結4_N(R22)_;其中R22係選自 氣或Ci · 6烧基；且 R與R21係獨立選自鹵基、氰基、羥基、胺甲醯基、甲 基、丙基、環丙基及甲氧基； 或其藥學上可接受之鹽或活體内可水解自旨。 因此，於本發明之進一步方面，係提供式①化合物（如上 文所描繪），其中： 環A為一氮七圜烷_3_基、（1α，5α，6α)_3_氮雙環并[3丄〇]己烷 -3-基、（R)-六氫吡啶各基、⑻_六氫吡啶氺基、六氫吡啶·4_ 基、四氫吡咯_3_基或内向各氮雙環并[3 21]辛净基； R1為氮上之取代基，且係選自氫、曱基、丙基、異丙基、 乙烯基磺醯基、甲烷磺醯基、苄氧羰基、第三-丁氧羰基、 乙醯基、苯乙基、乙氧It基、2_甲氧基乙基、胺確醯基、 120858 -40- 200811169 N，N-二甲基胺磺醯基、N，N-二甲基胺甲醯基、芊基、胺甲醯 基、N-曱基胺甲醯基、2-(二甲胺基）乙基磺醯基、2-(N-甲基-N-異丙基）乙基石黃S篮基、2-(1-甲基六氫u比ρ井-4-基）乙基續醯基、 2-四氳p比洛小基乙基績醯基、2-(3-氟基四氫卩比洛-1·基）乙基石黃 醯基、2-(硫代嗎福啉-4-基）乙基磺醯基、2-(4-甲基六氫吡啶-1-基）乙基磺醯基、2-(高六氫吡啶-1-基）乙基磺醯基、2-二乙胺 基乙基磺醯基、2-—氮四圜-1-基乙基磺醯基、2-嗎福啉基乙 基磺醯基、2-(4-氟基六氫吡啶-1-基）乙基磺醯基、2-(4-氰基六 氫吡啶-1-基）乙基磺醯基、2-(4-丙基六氫吡啶小基）乙基磺醯 基、2-(4-胺甲醯基六氫吡啶-μ基）乙基磺醯基、2-(7-氮雙環并 [2.2.1]庚-7-基）乙基磺醯基、2-(2-氮雙環并[2.2.2]辛-2-基）乙基磺 醯基、2-(6•氮雙環并[2.2.2]辛-6-基）乙基磺醯基、2-高嗎福啉基 乙基磺酸基、2-(2-酮基六氫吡畊冬基）乙基磺醯基、2-(1-乙醯 基六氫外!：_ -4-基）乙基磺醯基、2_(2_曱氧基乙胺基）乙基磺醯 基、2-(N-甲基-N·環丙基）乙基磺醯基、2-(2-酮基高六氫吡畊冬 基）乙基石買醯基、2-(1-乙醯基高六氫吡畊_4_基）乙基磺醯基、 2- (N-甲基-N-壞丙基甲基）乙基磺醯基、2_(高硫代嗎福啉冰基） 乙基磺醯基、3-氣基丙基磺醯基、3_二甲胺基丙基磺醯基、 3- —甲胺基-2,2-二甲基丙基磺醯基、3_二乙胺基丙基磺醯 基、3-(2-甲氧基乙胺基）丙基石黃醯基、ιγ·甲基_n_(2_甲氧基 乙基）胺基]丙基磺醯基、3_羥丙基磺醯基、3_(1_羥丙_2_基胺 基）丙基磺醯基、3-(1-曱基六氫吡啩冰基）丙基磺醯基、3_(l_ 異丙基六氫吡畊_4·基）丙基磺醯基、3_(6_氮雙環并[2·2·2]辛_6_ 基）丙基磺醯基、3-(7-氮雙環并[^谈々·基）丙基磺醯基、 120858 -41 - 200811169 3-[l-(2-羥乙基）六氫吡畊-4_基]丙基磺醯基、3_四氫吡咯小基丙 基磺醯基、3·(1，4_二甲基四氫吡咯小基）丙基磺醯基、3_嗎福 淋基丙基磺醯基、3-(1-羥基丁 -2-基胺基）丙基磺醯基、3-(1-甲氧基丙-2-基胺基）丙基磺醯基、3_(2_羥丙基胺基）丙基磺醯 基、3-(1-羥基-3-甲基丁 ·2-基胺基）丙基磺醯基、羥基_2-甲基丙-2-基胺基）丙基磺醯基、3_(六氫吡啶小基）丙基磺醯 基、3-(環丙胺基）丙基績醯基' 3-(Ν-甲基_Ν-環丙胺基）丙基磺 酸基、3-(環戊基胺基）丙基磺醯基、3_(Ν_甲基_Ν_環戊基胺基） 丙基磺醯基、3-(環丁基胺基）丙基磺醯基、3-(Ν-曱基環丁 基胺基）丙基磺醯基、3-(異丙基胺基）丙基磺醯基、3_(Ν_曱基 •Ν-異丙基胺基）丙基磺醯基、甲基乙胺基）丙基磺醯 基、3-[Ν-甲基善(2-氰基乙基）胺基]丙基磺醯基、3-[Ν-乙基 -Ν-(2-氰基乙基）胺基]丙基磺醯基、3一氮四圜小基丙基磺醯 基、3-(環丙基甲胺基）丙基磺醯基、3_(Ν-甲基_Ν_環丙基甲胺 基）丙基磺醯基、3-硝基-3-甲基丁基磺醯基、3-胺基-3-甲基丁 基績醯基、3-二甲基_3_甲基丁基磺醯基、2-(六氫吡啶-3-基） 乙酿基、2-(1-第三-丁氧羰基六氫吡啶_3_基）乙醯基、2_(六氫 峨咬-4-基）乙醯基、2-(1-第三-丁氧羰基六氫吡啶-4-基）乙醯 基 2 —曱胺基乙酿基、3-(1-第二-丁氧幾基六氮说哨* -4-基） 丙醢基、3-(1-第三-丁氧羰基六氫吡啶冬基）丙醯基、3_(六氫 峨咬-4-基）丙醯基、3-(六氫吡畊-4-基）丙醯基、3-二甲胺基丙 醯基、4-嗎福啉基丁醯、4_二甲胺基丁醯基、；μ第三-丁氧羰 基-4-甲基六氫吡啶_4_基羰基、本甲基六氫吡啶斗基羰基、μ 弟二-丁氧魏基-4-甲基六氫Ϊ7比σ定-4-基幾基、4-甲基高六氫外匕 120858 -42- 200811169 畊_1·基羰基、1-甲基六氫吡啶-3-基羰基、1·甲基四氫吡咯_2-基羰基、3-二甲胺基四氫吡咯小基羰基、4-第三-丁氧羰基嗎 福P林-2-基魏基、嗎福淋-2-基幾基、1-甲基六氫U比σ定-4-基胺甲 醯基、N-(l-乙基四氫吡咯-2_基甲基）胺曱醯基、Ν-(2-四氫吡 咯-1·基乙基）胺甲醯基、Ν-(2_二甲胺基乙基）胺甲醯基、N_(l-甲基六氫吡啶-4-基）胺磺醯基、N-(l-異丙基六氫吡啶-4_基）胺 磺醯基、2-(二甲胺基）乙基胺磺醯基、2_(二乙胺基）乙基胺磺 醯基、2-(嗎福啉基）乙基胺磺醯基、2-(1_甲基六氫吡畊冰基） 乙基胺磺醯基、2-(1_甲基四氫吡咯·2_基）乙基胺磺醯基、3-(四 氫峨洛基）丙基胺磺醯基、3_(3_氟基四氫吡咯小基）丙基胺 貝酿基3-一甲胺基-2,2-一曱基丙基胺石黃酿基、3·(六氫ρ比σ定 小基）丙基胺磺醯基、Ν-甲基-Ν-(3·二甲胺基丙基）胺磺醯基、 3-—甲胺基四氫吡咯—μ基磺醯基、^甲基六氫吡畊_4_基磺醯 基、1-甲基六氳吡啶-4-基磺醯基、1-異丙基六氫吡啶冰基磺 酉藍基及1-甲基高六氫吡畊冰基磺醯基； q為0 ; R3為氟基或氣基； η為0或1 ; R4係選自異丙基或環戊基； R5為甲基； 或其藥學上可接受之鹽或活體内可水解酯。 於本發明之另一方面，本發明之較佳化合物為實例之任 、或其篥學上可接受之鹽或活體内可水解酯。 於本發明之進一步方面’特定化合物為實例⑵、別、 120858 -43- 200811169 140、142、144、1仏 145 、 146 、 149 、 15〇 或 187 之 藥學上可接受之鹽或活體内可水解醋。 項，或其 本^之較㈣面料與㈣化合物 上可接受之鹽。 乂一系學 才法㈤使式（II)嘧啶： 本毛月之另一方面係提供一種製備式（I)化合物或其藥學 上可接文之鹽或活體内可水解酯之方法，此方法（其中可變 基團’除非另有指明，否則係如式⑴中所定義者)包括：%8 is a 5- or 6-membered saturated heterocyclic ring containing a nitrogen atom; wherein two atoms of ring A 120858 -34- 200811169 may be optionally joined by a bridging group; R1 is a substituent on the nitrogen and is selected from hydrogen, Ci-6 alkyl, Ci_6 alkyl fluorenyl, amine methyl sulfonyl, Ν-θ υ alkyl) amine methyl sulfonyl, N, N-(Ch alkyl) amine methyl sulfhydryl, amine sulfonyl, Ν-(( ^ _6 alkyl)amine sulfonyl, ν, _ 6 alkyl) 2 amine sulfonyl, Cl·6 oxyzinc, Cn alkylsulfonyl, Ci-6 fluorenyl or heterocyclic Wherein R1 may be optionally substituted on the carbon with one or more R8; and wherein if the heterocyclic group contains a moiety, the nitrogen may be optionally substituted with a group selected from r9; q is 0; R3 is i group; η is 0 or 1; R4 is selected from isopropyl or cyclopentyl; R5 is methyl; R7 is selected from -C(O)-, -C(0)N(R15)-, -S(0)2- or -S02N(R16)-; wherein R15 and R16 are hydrogen; R8 is selected from the group consisting of halo, nitro, hydroxy, amine, alkyl, Cle6 alkoxy, NA.6 alkyl An amine group, an n,N-(Ch alkyl) 2 amine group, a carbocyclic group or a heterocyclic group -R 18 -; wherein R 8 may optionally be substituted on the carbon by one or more R 9 , and wherein The heterocyclic group contains a -NH- moiety, and the nitrogen may be optionally substituted with a group selected from R 2 G; the R 9 and R 2 G systems are independently selected from the group consisting of Cl. 6 alkyl, Cl 0 alkyl fluorenyl, Cl· 6 alkoxycarbonyl and benzyloxycarbonyl; wherein R9 and r2 are independently substituted with one or more R21 on the carbon, as the case may be; R17 and R18 are independently selected from the direct bond 4_N (R22); wherein R22 is selected From 120858 to 35-200811169 hydrogen or alkyl; and R19 and R21 are independently selected from halo, cyano, hydroxy, aminemethanyl, methyl, propyl, cyclopropyl and methoxy; or pharmaceutically thereof An acceptable salt or in vivo hydrolysable ester. Thus, in a further aspect of the invention, there is provided a compound of formula 1 (as depicted above) wherein: ring A is (1 α,5 α,6 a )-3- Nitrobicyclo and P.1.0]hexane-3-yl, (R)-hexahydropyridin-3-yl, (S)-hexahydropyridine, hexahydropyridyl-4-yl, tetrahydropyrrole-3 a radical or an inward-8-azabicyclo[3.2.1]oct-3-yl; R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, methyl, propyl, isopropyl, vinyl fluorenyl, hydrazine Calcination thiol, benzyloxycarbonyl, tert-butoxycarbonyl Ethyl, phenethyl, ethoxycarbonyl, 2-decyloxyethyl, sulfonyl, N,N-dimethylamine sulfonyl, n,N-didecylamine, benzyl, benzyl Base, amine mercapto, N-methylamine, mercapto, 2-(diamido)ethylsulfonyl, 2-(N-methyl-N-isopropyl)ethyl sulphate, 2- (1-methylhexahydropyridin-4-yl)ethyl fluorenyl, 2-tetrapyran-1-ylethyl fluorenyl, 2-(3·fluoroyltetradecyl) Ethyl pyridyl, 2-(thiomorpholine-4-yl)ethylsulfonyl, 2-(4-methylhexahydropyridyl)ethylsulfonyl, 2-(high hexahydro Pyridin-1-yl)ethylsulfonyl, 2-diethylaminoethylsulfonyl, 2-nitrotetradec-1-ylethylsulfonyl, 2-morpholineethylsulfonate Base, 2-(4-fluorohexahydropyridin-1-yl)ethyl sulfonyl, 2-(4-cyanohexahydroinden-1-yl)ethyl decyl, 2·(4· Propyl hexahydroindole 1-1 yl) ethyl decyl, 2-(4. amine carbaryl hexahydropyridin-1-yl) ethyl sulfonyl, 2 _, nitrogen bicyclo[2.2. 1]hept-7-yl)ethylsulfonyl, 2-(2-azabicyclo[2.2.2]oct-2-yl)ethylsulfonyl, 2-(6-azabicyclo) [2.2.2] oct-6-yl)ethylsulfonyl, 2-high porphyrinyl 120858-36 - 200811169 Ethylsulfonyl, 2-(2-ketohexahydropyrazole-4-yl Ethyl sulfonyl, 2-(1-ethylindenylhexahydropyranyl) ethylsulfonyl, 2-(2-methoxyethylamino)ethylsulfonyl, 2-(N -methyl-N-cyclopropyl)ethylsulfonyl, 2-(2-keto-high hexahydropyridyl)ethyl-stone-brewed base, 2-(1-ethyl-branched South-six-mouse p ratio -Phenyl-4-yl)ethyl stellate, 2-(N-fluorenylcyclopropylmethyl)ethylsulfonyl, 2-(high thiomorphine-4-yl)ethyl continuation , 3-air-based propyl alcohol, 3-dimethylaminopropyl schistosamine, 3-dimethylamino-2,2-dimethylpropylsulfonyl, 3-diethylaminopropyl Sulfosyl, 3-(2-methoxyethylamino)propyl fluorenyl, 3-[N-methylmethoxyethyl)amino]propyl phosphazenyl, 3-propyl sulfonium, 3-(1-propan-2-ylamino)propylsulfonyl, 3-(1-indenylhexahydro-7-4-yl)propyl, 3-(1-isopropyl Hexahydropyrrolidyl)propylsulfonyl, 3-(6-azabicyclo[2.2.2]oct-6-yl)propylsulfonyl, 3-(7-azabicyclo[2.2. 1]hept-7-yl)propylsulfonyl, 3-[1-(2-ethyl)hexahydro-b-flavor·4-yl]propyl-propyl, 3-tetra-exo-bp 1-ylpropyl sulphate, 3-(1,4-dimethyltetrahydro-p-l-yl-1-yl)propyl fluorescein, 3-oxabulinylpropylsulfonyl, 3-(1- Hydroxybutan-2-ylamino)propylsulfonyl, 3-(1-decyloxypropan-2-yl)propylsulfonyl, 3-(2-hydroxypropylamino)propyl Sulfosyl, 3-(1-carbo-3-methylbutan-2-ylamino)propylglycosyl, 3-(1-carbo-2-methylpropan-2-ylamino)propyl Benzyl, 3-(hexahydroindol-1-yl)propylglycosyl, 3-(cyclopropylamino)propylsulfonyl, 3-(N-methyl-N-cyclopropylamino)propylsulfonate Mercapto, 3-(cyclopentylamino)propylsulfonyl, 3-(N-methylcyclopentylamino)propylsulfonyl, 3-(cyclobutylamino)propylsulfonate , 3-(N-methyl-N-cyclobutylamino)propylsulfonyl, 3-(isopropylamino)propylsulfonyl, 3-(N-methyl-N-iso Propylamino)propylsulfonyl, 3-(N-methylethylamino)propylsulfonyl, 3-[N-methyl-N-(2-cyanoethyl)amino]propyl Cornerstone xanthine, 3-[N-ethyl 120858 -37- 200811169 -N-(2-cyanoethyl)amino]propylsulfonyl, 3-nitrozinium-4-propylsulfonyl>(cyclopropylmethylamino)propyl stone Astragalus, 3-(N-methyl-N-cyclopropylmethylamino)propyl sulphate, 3-nitro-3-methylbutylglycosyl, 3-amino-3-methylbutylsulfonate Mercapto, 3-dimethyl-3-mercaptobutylsulfonyl, 2-(hexahydropyridine)ethylidene, 2·(1-tert-butoxycarbonylhexahydropyridine-3-yl) Ethyl thiol, 2-(hexahydroperoxy-4-yl)ethenyl, 2-(1-tert-butoxycarbonylhexahydropyridyl)ethenyl, 2-diaminoaminoethyl Base, 3-(1_3rd-butoxycarbonylhexahydropyrrolidyl) propyl sulfhydryl, 3_(1_t-butoxycarbonylhexahydropyridyl) propyl sulfhydryl, 3_(hexahydro external 4-yl)propanyl, 3-(hexahydropyrrolidin-4-yl)propanyl, 3-dimethylaminopropynyl, 4-fosfo-4-ylbutyrate, 4-dimethylamino Butyl sulfonate, μ, tert-butoxycarbonyl-4-mercaptohexahydropyridyl carbonyl, 4·methylhexahydropyridyl carbonyl, 1-di-di-butoxy-yl-4-mercaptohexahydropred -4-Kidyl, 4-methyl, hexahydro-p, plough-1, carbonyl, 1-methyl Hexahydropyridine-3-ylcarbonyl, 1-hydrazinotetrahydropyrrole-2-ylcarbonyl, 3-dimethylaminotetrahydropyrrole-y-ylcarbonyl, 4-tris-butoxycarbonyl-n-carboline-2- Carbo group, moffolin-2-yl-Weiyl, 1-methylhexahydroindole-4-ylaminecarbamyl, oxime (1-ethyltetrahydropyrrole-2-ylmethyl)amine A Indenyl, N-(2-tetrahydropyrrol-1-ylethyl)amine, mercapto, N-(2-dimethylaminoethyl)amine, mercapto, N-(l-methylhexahydropyridine, 4 Amine sulfonyl, N-(l-isopropylhexahydropyridin-4-yl)amine sulfonyl, 2-(diguanidino)ethylamine sulfonyl, 2-(diethylamine Ethylamine sulfonyl, 2-(morpholino)ethylamine sulfonyl, 2-(1-methylhexahydropyrryl-4-yl)ethylamine benzyl, 2-( 1·Methyltetrahydropyrrol-2-yl)ethylamine sulphate, 3-(tetrahydro-exo 17 17-yl)propylamine sulphate, 3-(3-fluoro-tetrahydro-p-bi -1-yl)propylamine sulfonyl, 3-dimethylamino-2,2-dimercaptopropylsulfonyl, 3-(hexahydropyridin-1-yl)propylamine sulfonyl , N-fluorenyl-N-(3-dimethylaminopropyl)amine sulfonyl, 120858 -38 - 200811169 3-methylaminotetrahydropyrrole + sulfonate Base, 丨-methylhexahydropyridinylsulfonyl, 1-methylhexahydropyridylsulfonyl, μisopropylhexahydropyridylsulfonylsulfonyl and methylhexahydropyridinium a sulfhydryl group; q is 0; R3 is a fluoro or chloro group; η is 0 or 1; R4 is selected from isopropyl or cyclopentyl; R5 is methyl; or a pharmaceutically acceptable salt thereof or Hydrolyzable esters in vivo. Thus, in a further aspect of the invention, there is provided a compound of formula 1 (such as green as described above) wherein: 裱8 is a 5-7 membered saturated heterocyclic ring containing a nitrogen atom; wherein an atom of the ring VIII can be bridged as appropriate R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, Ci 6 alkyl, 6 alkyl fluorenyl, amine carbaryl, fluorene-((ν6 alkyl)amine carbhydryl, n, n_(Ci -6 alkyl)amine carbenyl, sulfonyl, Ν-((^ _6 alkyl)amine sulfonyl, N,N_(Ci ·6 alkyl) 2 amine sulfonyl 'A·6 alkane An oxycarbonyl group, a Ci-0 alkylsulfonyl group, a Ci 6 alkenylsulfonyl group or a heterocyclic group -R7; wherein R1 may be optionally substituted on the carbon with one or more R8; and wherein if the 4% by weight group contains - a nh_partial group, the nitrogen may optionally be substituted by a group selected from R9; q is 0; R3 is a _ group; η is 0 or 1; R4 is selected from isopropyl or cyclopentyl; 39- 200811169 R5 is a fluorenyl group; R7 is selected from -C(O)-, _s(0)2 or 〇2N(Rl6); wherein R15 and R16 are hydrogen; R8 is selected from a group and a nitro group. , hydroxy, amine, Ci 6 alkyl, Ci 6 alkoxy, n-(Ch alkyl)amine, N,N-(C-6 alkyl 2Amino, carbocyclyl or ethyl or heterocyclyl-R18-; wherein R8 may be optionally substituted on the carbon with one or more Rl9, and wherein if the heterocyclyl contains a beta group, the nitrogen Optionally, it is substituted by a group selected from R20; R and R are independently selected from the group consisting of a calcinyl group, a c-pyrazine group, a pyridyloxycarbonyl group, and a benzyloxycarbonyl group; wherein R9 and r2g are independently of each other, as the case may be. Substituting one or more R21 on carbon; R17 and RU are independently selected from direct bond 4_N(R22)_; wherein R22 is selected from gas or Ci-6 alkyl; and R and R21 are independently selected from halo , cyano, hydroxy, carbamoyl, methyl, propyl, cyclopropyl and methoxy; or a pharmaceutically acceptable salt thereof or hydrolyzable in vivo. Thus, in a further aspect of the invention, Providing a compound of formula 1 (as depicted above) wherein: ring A is nitros-7-yl, (1α, 5α, 6α)_3_azabicyclo[3丄〇]hexane-3-yl , (R)-hexahydropyridine, (8)-hexahydropyridinium, hexahydropyridyl-4-yl, tetrahydropyrrole-3-yl or inwardly nitrogenybicyclo[3 21]octyl; R1 is nitrogen Substituent, and selected from , mercapto, propyl, isopropyl, vinylsulfonyl, methanesulfonyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethyl phenyl, phenethyl, ethoxy-based, 2-methoxy Ethyl ethyl, amine sulfhydryl, 120858 -40- 200811169 N,N-dimethylamine sulfonyl, N,N-dimethylamine, fluorenyl, fluorenyl, carbamoyl, N-fluorenyl Aminomethyl thiol, 2-(dimethylamino)ethylsulfonyl, 2-(N-methyl-N-isopropyl)ethyl sulphate S basket, 2-(1-methylhexahydrou ρ -4--4-yl)ethyl fluorenyl, 2-tetramethylene p-pyridyl ethyl fluorenyl, 2-(3-fluoro-tetrahydropyridyl-1 -yl)ethyl sulphate, 2-(Thiofosolin-4-yl)ethylsulfonyl, 2-(4-methylhexahydropyridin-1-yl)ethylsulfonyl, 2-(high hexahydropyridine-1- Ethylsulfonyl, 2-diethylaminoethylsulfonyl, 2-nitrotetradec-1-ylethylsulfonyl, 2-morpholineethylsulfonyl, 2- (4-Fluorohexahydropyridin-1-yl)ethylsulfonyl, 2-(4-cyanohexahydropyridin-1-yl)ethylsulfonyl, 2-(4-propylhexahydropyridine Small base) ethylsulfonyl, 2-(4-aminomethylpyridinylhexahydropyridine-μ)ethylsulfonate , 2-(7-azabicyclo[2.2.1]hept-7-yl)ethylsulfonyl, 2-(2-azabicyclo[2.2.2]oct-2-yl)ethylsulfonyl , 2-(6•azabicyclo[2.2.2]oct-6-yl)ethylsulfonyl, 2-homomorpholinylethylsulfonate, 2-(2-ketohexahydropyrazine Ethyl sulfonyl, 2-(1-ethenylhexahydroexo!: -4-methyl)ethylsulfonyl, 2-(2-methoxyethyl)ethylsulfonyl , 2-(N-methyl-N-cyclopropyl)ethylsulfonyl, 2-(2-keto-high hexahydropyrazine) ethyl-stone-purinyl, 2-(1-ethenyl) High hexahydropyridinium_4_yl)ethylsulfonyl, 2-(N-methyl-N-propanylmethyl)ethylsulfonyl, 2-(high thiomorpholine ice-based) Sulfosyl, 3-apropylpropylsulfonyl, 3-dimethylaminopropylsulfonyl, 3-methylamino-2,2-dimethylpropylsulfonyl, 3_two Ethyl propyl sulfonyl, 3-(2-methoxyethylamino) propyl fluorenyl, ιγ·methyl_n_(2-methoxyethyl)amino]propylsulfonyl, 3 _Hydroxypropylsulfonyl, 3_(1_hydroxypropan-2-ylamino)propylsulfonyl, 3-(1-decylhexahydropyridinium)propylsulfonyl, 3_(l_ Isopropyl Hydrogen pyridinium _4·yl)propylsulfonyl, 3_(6-azabicyclo[2·2·2]octyl-6-yl)propylsulfonyl, 3-(7-nitrobicyclo[^丙基·yl)propylsulfonyl, 120858 -41 - 200811169 3-[l-(2-hydroxyethyl)hexahydropyrazine-4_yl]propylsulfonyl, 3_tetrahydropyrrole Sulfosyl, 3,(1,4-dimethyltetrahydropyrroleyl)propylsulfonyl, 3-norfosylpropylsulfonyl, 3-(1-hydroxybutan-2-yl Amino)propylsulfonyl, 3-(1-methoxypropan-2-ylamino)propylsulfonyl, 3-(2-hydroxypropylamino)propylsulfonyl, 3-( 1-hydroxy-3-methylbutan-2-ylamino)propylsulfonyl, hydroxy-2-methylpropan-2-ylamino)propylsulfonyl, 3-(hexahydropyridine small) Propylsulfonyl, 3-(cyclopropylamino)propylmethyl] 3-(indolyl-methyl-indole-cyclopropylamino)propylsulfonate, 3-(cyclopentylamino)propyl Sulfonyl, 3_(Ν_methyl_Ν_cyclopentylamino)propyl sulfonyl, 3-(cyclobutylamino)propylsulfonyl, 3-(fluorenyl-fluorenylcyclobutyl Amino)propylsulfonyl, 3-(isopropylamino)propylsulfonyl, 3-(indolyl-indole-isopropylamino)propylsulfonate Methylethylamino)propylsulfonyl, 3-[indolyl-(2-cyanoethyl)amino]propylsulfonyl, 3-[indolyl-indole-( 2-cyanoethyl)amino]propylsulfonyl, 3-nitrotetramethylenesulfonyl, 3-(cyclopropylmethylamino)propylsulfonyl, 3_(Ν-甲Ν_Ν_cyclopropylmethylamino)propylsulfonyl, 3-nitro-3-methylbutylsulfonyl, 3-amino-3-methylbutylbenzyl, 3-dimethyl _3_Methylbutylsulfonyl, 2-(hexahydropyridin-3-yl)ethyl, 2-(1-tris-butoxycarbonylhexahydropyridine-3-yl)ethenyl, 2_ (hexahydrozepine-4-yl)ethyl hydrazino, 2-(1-tris-butoxycarbonylhexahydropyridin-4-yl)ethyl hydrazino 2 -nonylaminoethyl, 3-(1- Second-butoxy hexyl hexanitro sulphide * -4-yl) propyl fluorenyl, 3-(1-tris-butoxycarbonyl hexahydropyridylpyridyl) propyl sulfhydryl, 3 _ hexahydro hydrazine bite-4 -yl)propanyl, 3-(hexahydropyroxy-4-yl)propanyl, 3-dimethylaminopropynyl, 4-morpholinylbutanyl, 4-dimethylaminobutanyl, ;μT-butoxycarbonyl-4-methylhexahydropyridine_4-carbonyl, this methylhexahydropyridine carbonyl, μ di-butoxy Wei Ke-4-methylhexahydroindole 7 is more specific than sigma-4-yl, 4-methyl hexahydroindole 120858 -42- 200811169 耕_1· carbonyl, 1-methylhexahydropyridine-3 -ylcarbonyl, 1·methyltetrahydropyrrole_2-ylcarbonyl, 3-dimethylaminotetrahydropyrroleylcarbonyl, 4-tris-butoxycarbonyl-based P-phenyl-2-yl-Weiyl, Fulin-2-yl benzyl, 1-methylhexahydro-U sigma-4-ylaminocarbazinyl, N-(l-ethyltetrahydropyrrole-2-ylmethyl)amine fluorenyl, Ν-(2-tetrahydropyrrole-1.ylethyl)aminecarboxymethyl, fluorenyl-(2-dimethylaminoethyl)aminecarboxymethyl, N-(l-methylhexahydropyridin-4-yl Aminesulfonyl, N-(l-isopropylhexahydropyridin-4-yl)amine sulfonyl, 2-(dimethylamino)ethylamine sulfonyl, 2-(diethylamino) Acesulfame, 2-(morpholine)ethylaminesulfonyl, 2-(1-methylhexahydropyrrolidyl)ethylaminesulfonyl, 2-(1-methyl-4- Hydropyrrole·2—yl)ethylamine sulfonyl, 3-(tetrahydrofurfuryl)propylamine sulfonyl, 3-(3-fluorotetrahydropyrrole small)propylamine styrene 3- Monomethylamino-2,2-mercaptopropylamine yellow wine, 3·(hexahydroρ ratio σ定小基)propylamine sulfonate Base, Ν-methyl-hydrazine-(3. dimethylaminopropyl)amine sulfonyl, 3-methylaminotetrahydropyrrole-μ-sulfonyl, methyl hexahydropyrrol _4_ Sulfosyl, 1-methylhexapyridine-4-ylsulfonyl, 1-isopropylhexahydropyridyl glacial sulfonium blue and 1-methylhexahydropyrrolidylsulfonyl; q is 0; R3 is a fluorine group or a gas group; η is 0 or 1; R4 is selected from isopropyl or cyclopentyl; R5 is a methyl group; or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo. In another aspect of the invention, preferred compounds of the invention are any of the examples, or a salt thereof or a hydrolyzable ester in vivo. In a further aspect of the invention, the specific compound is a pharmaceutically acceptable salt of Example (2), another, 120858-43-200811169 140, 142, 144, 1仏145, 146, 149, 15〇 or 187 or hydrolyzable in vivo. vinegar. Item, or its equivalent to (4) fabric and (iv) a salt acceptable for the compound. A method for the preparation of a pyrimidine of the formula (II): a further aspect of the present invention provides a method for preparing a compound of the formula (I) or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo. (wherein the variable group 'as defined in formula (1) unless otherwise indicated) includes:

(II) 與式（III)苯胺反應(II) Reaction with aniline of formula (III)

其中L為可置換基團 或 才法Θ使式（IV)化合物：Wherein L is a displaceable group or a compound of formula (IV):

與式（V)化合物反應： 120858 -44- (IV) X200811169 (R3)Reaction with a compound of formula (V): 120858 -44- (IV) X200811169 (R3)

Rx ηRx η

R4、R4,

其中T為0或s; (V) 或Where T is 0 or s; (V) or

Rx可為相同或不同，且係選自c1-6烷基 才法Θ使式（VI)嘧。定··Rx may be the same or different and is selected from the group consisting of c1-6 alkyl to give pyrimidine of formula (VI). set··

Y (R2)qY (R2)q

R1 (VII) 其中Y為可置換基團； 及接著若必要，則： 0使式（1)化合物轉化成另一種式（I)化合物； ϋ) 移除任何保護基； in)形成藥學上可接受之鹽或活體内可水解酯。 L為可置換基團，關於L之適當意義為例如鹵基或磺醯基 120858 -45- 200811169 氧基，例如氣基、溴基、甲烷磺醯基氧基或甲苯冬磺醯基 氧基。 、土 Y為可置換基團，關於γ之適當意義為例如齒基或績醯基 氧基’例如溴基、碘基或三氟甲烷磺醯基氧基。Y較佳為 硬基。 關於上述反應之特定反應條件如下。 方法可使式（π)嘧啶與式（HI)苯胺，在適當溶劑中一起 反應，譬如四氫呋喃、N-甲基四氫吡咯g同或異丙醇，或可 不含溶劑一起反應，在25-200°C範圍之溫度下，特別是在 6(M60°C之範圍内。反應可於適當鹼存在下進行，例如n，n_ —異丙基乙胺、氫化納或碳酸卸。 式（II)吻、咬類’其中L為氯基’可根據屬式/製備·R1 (VII) wherein Y is a displaceable group; and if necessary: 0 converts a compound of formula (1) to another compound of formula (I); ϋ) removes any protecting group; in) forms a pharmaceutically acceptable Accepted salts or hydrolyzable esters in vivo. L is a displaceable group, and a suitable meaning for L is, for example, a halo or sulfonyl group 120858-45-200811169 oxy group such as a gas group, a bromo group, a methanesulfonyloxy group or a tolylsulfonyloxy group. And soil Y is a replaceable group, and a suitable meaning for γ is, for example, a dentate group or a fluorenyloxy group such as a bromo group, an iodo group or a trifluoromethanesulfonyloxy group. Y is preferably a hard base. The specific reaction conditions regarding the above reaction are as follows. The method can react the (π)pyrimidine with the formula (HI) aniline in a suitable solvent, such as tetrahydrofuran, N-methyltetrahydropyrrole g or isopropanol, or can react without solvent, at 25-200 In the range of °C, especially in the range of 6 (M60 ° C. The reaction can be carried out in the presence of a suitable base, such as n, n-isopropylethylamine, sodium hydride or carbonic acid. Formula (II) kiss , bite class 'where L is chlorine base' can be based on the genus / preparation

NaN〇2， HCl(^c 溶液)NaN〇2, HCl (^c solution)

圖式1 式（III)胺類係為市購可得之化合物，或豆係务 τ、馬文獻上已 !2〇858 -46- 200811169 知，或其係藉由此項技藝中已知之標準方法製備。 方，使式（IV>化合物與式（V)化合物一起反應，於適當 合背丨中言如N-甲基四氫吡咯酮或丁醇，在1〇〇_2〇〇。〇範圍之 温度下，較佳係在购7(TC之範圍内。反應較佳係於適當 驗存在下進行，例如氫化納、甲醇納或碳酸卸。 式（V)化合物可根據鏍式2製備：The amines of the formula (III) are commercially available compounds, or the Beans τ, the horse literature has been published! 2〇858-46- 200811169 know, or it is by the standards known in the art Method preparation. Further, a compound of the formula (IV) is reacted with a compound of the formula (V) in a suitable backing such as N-methyltetrahydropyrrolidone or butanol at a temperature of 1 〇〇 2 〇〇. Preferably, the reaction is carried out in the range of 7 (TC). The reaction is preferably carried out in the presence of a suitable test, such as sodium hydride, sodium methoxide or carbonic acid. The compound of formula (V) can be prepared according to formula 2:

MeMgBr, THF -20°CMeMgBr, THF -20 ° C

Μη02 (V) 1 DMFDMA，△ 二氧陸圜 △Μη02 (V) 1 DMFDMA, △ Dioxane △

圖式2 式（IV)與（ya)化合物係為市講可得之化合物，或其 獻上已知，或其係藉由此項技藝中已知之標準方法製備。 才扣τ使式π)%合物與式_胺類纟才法…斤述 之條件下一起反應。 八（VI)化合物 3成係描述於屬4、τ。 化合物係為市購可得之化合物，或其係為文獻上 ° ’或其係藉由此項技藝中已知之標準方法製備。 :明：”，於本發明化合物中之某些不同環取代基， 错由裇準方香族取代反應引進，或藉習用官能基修正而 120858 -47- 200811169 產生，無論是在上文所提及方法之前或緊接於後，且其本 身係被包含在本發明之方法方面中。此種反應與修正包括 例如利用芳香族取代反應引進取代基、取代基之還原作 用、取代基之烷基化作用及取代基之氧化作用。關於此種 程序之試劑與反應條件，係為化學技藝上所習知。芳香族 取代反應之特定實例，包括使用濃硝酸引進硝基，使用例 如齒化酿與路易士酸（譬如三氯化鋁）於Friedel Crafts條件下 引進醯基；使用烷基鹵化物與路易士酸（譬如三氯化鋁）於 Friedel Crafts條件下引進烷基；及引進鹵基。修正之特定實 例’包括使硝基還原成胺基，其方式是例如使用鎳觸媒進 行催化氫化，或使用鐵，於鹽酸存在下處理，伴隨著加熱； 使烧k基氧化成烧基亞績酿基或烧基確酿基。 亦應明瞭的是，在本文中所提及之一些反應中，可能必 須/想要保遵化合物中之任何敏感性基團。其中必須或想要 保護之情況，及關於保護之適當方法，係為熟諳此藝者所 已知。習用保護基可根據標準實務使用（關於說明可參閱 T.W· Green，有機合成上之保護基，j〇hn Wiley & Sons，1991)。因 此，若反應物包含一些基團，譬如胺基、羧基或羥基，則 一般可能期望在本文所提及之一些反應中保護此基團。 對於胺基或烷胺基之適當保護基，係為例如醯基，例如 烷醯基，譬如乙醯基，烷氧羰基，例如甲氧羰基、乙氧幾 基或第三-丁氧羰基，芳基甲氧羰基，例如苄氧羰基，或芳 醯基，例如苯甲醯基。關於上文保護基之去除保護條件， 必須隨著保護基之選擇而改變。因此，例如醯基，譬如燒 120858 -48- 200811169 基，或炫氧幾基或芳醯基，可藉由例如水解作用，使用 適當鹼，譬如鹼金屬氫氧化物，例如氫氧化鋰或鈉，而被 移除。或者，醯基，譬如第三_τ氧幾基，可藉由例如以適 當酸譬如鹽酸、硫酸或構酸或三氟醋酸處理而被移除，及 芳基甲氧氣基’譬如爷氧幾基，可例如於觸媒譬如把/碳上， 藉由氫化作用，或經由以路易士酸例如參（三氟醋酸）爛處 理’而被移除。對於一級胺基之適當替代保護基為例如酉太 醯基’其可經由以烷基胺’例如二甲胺基丙胺，或以胼處 理而被移除。 對於螽基之適當保護基為例如醯基，例如烷醯基，譬如 乙醯基，芳醯基，例如苯甲醯基，或芳基甲基，例如爷基。 關於上文保善基之去除保護條件，係、必須尸遺著保護基之選 擇而改變。因此，例如醯基，譬如烧酿基或芳隨基可藉由 例如水解作用，使用適當驗，譬如驗金屬氯氧化物，例如 氫氧化鋰或鈉，而被移除。或者，芳基甲基，譬如苄基， 可例如使用觸媒譬如鈀/碳，藉由氫化作用而被移除。 對於羧基之適當保護基係為例如酯化基團，例如甲基戋 乙基，其可例如使用鹼，譬如氫氧化鈉，藉由水解作用， 而被移除，或例如第三-丁基，其可例如使用酸，例如有機 酸，譬如三氟醋酸處理，而被移除，或例如苄基，其可例 如使用觸媒，譬如乾/碳，藉由氫化作用而被移除。 保護基可在合成中之任何合宜階段下，使用化學技藝上 習知之習用技術移除。 如前文所述’於本發明中定義之化合物係具有抗細胞增 120858 -49- 200811169 生活性，譬如抗癌活性，咸信其係源自於此化合物之CDK 抑制活性。此等性質可被評估，例如使用下文所詳述之程 序.-檢測 已使用下列縮寫：- HEPES為N-[2-羥乙基]六氫吡畊-Nf-[2_乙烷磺酸] DTT為二硫基蘇糖醇 PMSF為苯基甲基氟化磺醯 化合物係在活體外激酶檢測中測試，於96井格式中，使 用閃爍親近檢測（SPA -得自Amersham)，以度量[r-33-P]·腺甞 三磷酸之併入試驗受質（GST-視網膜胚細胞瘤蛋白質； GST-Rb)中。於各井中放置欲被測試之化合物（於DMSO與水 中稀釋，以校正濃度），且於對照井中放置無論是作為抑制 劑對照組之洛斯可維丁（roscovitine)或作為正對照組之 DMSO 〇 將已被稀釋於25微升培養缓衝劑中之大約0·2微升CDK2/ 環素Ε部份純化酵素（量依酵素活性而定）添加至各井中， 然後是20微升GST-Rb/ATP/ATP33混合物（含有0.5微克GST_Rb 與0.2 //Μ ATP及0.14 //Ci[ r-33-P]-腺甞三磷酸，在培養緩衝劑 中），並將所形成之混合物溫和地振盪，然後在室溫下培養 60分鐘。The compounds of formula (IV) and (ya) are commercially available compounds, or are known, or are prepared by standard methods known in the art. Only τ is added to make the π)% compound react with the formula _ amine 纟 method. The compound of the eight (VI) compound is described in the genus 4, τ. The compound is a commercially available compound, or is in the literature or is prepared by standard methods known in the art. :明:", some of the different ring substituents in the compounds of the present invention, which are introduced by the 裇 方 香 香 取代 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And the method is preceded or immediately after, and is itself included in the method aspect of the present invention. Such reactions and modifications include, for example, introduction of a substituent by an aromatic substitution reaction, reduction of a substituent, alkyl group of a substituent The oxidizing action of the substituents and the substituents. The reagents and reaction conditions for such a procedure are well known in the art of chemistry. Specific examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, using, for example, toothed brewing. Lewis acid (such as aluminum trichloride) is introduced into the sulfhydryl group under the condition of Friedel Crafts; the alkyl group is introduced with Lewis acid (such as aluminum trichloride) under Friedel Crafts conditions; and the halogen group is introduced. Specific examples of 'reducing a nitro group to an amine group by catalytic hydrogenation using, for example, a nickel catalyst, or using iron, in the presence of hydrochloric acid, with heating Oxidation of the k-based group to the alkyl group or the alkyl group. It should also be understood that in some of the reactions mentioned herein, it may be necessary/want to follow any sensitive groups in the compound. The regimen, which must or may be protected, and the appropriate method of protection are known to those skilled in the art. The customary protecting group can be used according to standard practice (for instructions, see TW·Green, Protection of Organic Synthesis). Base, j〇hn Wiley & Sons, 1991). Thus, if the reactants contain groups such as amine groups, carboxyl groups or hydroxyl groups, it may generally be desirable to protect the groups in some of the reactions mentioned herein. A suitable protecting group for an amino or alkylamino group is, for example, a fluorenyl group, such as an alkane group, for example an ethoxy group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxylated group or a tert-butoxycarbonyl group, an aryl group. A methoxycarbonyl group, such as a benzyloxycarbonyl group, or an aryl fluorenyl group, such as a benzylidene group. With regard to the removal protection conditions of the above protecting group, it must be changed with the choice of the protecting group. Thus, for example, a sulfhydryl group, such as calcined 120858 - 48- 200811169 Or a oxyl group or an aryl group, which may be removed by, for example, hydrolysis, using a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. Alternatively, a sulfhydryl group such as a third _τ The oxygen group can be removed by, for example, treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phytic acid or trifluoroacetic acid, and an arylmethyloxy group such as an oxo group, for example, a catalyst such as a carbon/carbon Is removed by hydrogenation or by treatment with a Lewis acid such as ginsine (trifluoroacetic acid). Suitable replacement protecting groups for the primary amine group are, for example, anthracene, which can be via an alkylamine. 'eg dimethylaminopropylamine, or removed by treatment with hydrazine. Suitable protecting groups for fluorenyl are, for example, fluorenyl, such as alkyl, such as ethyl, aryl, for example, benzhydryl, or An arylmethyl group, such as a aryl group. Regarding the conditions for the removal of protection from the above, the system must be changed by the choice of the protection base. Thus, for example, a sulfhydryl group, such as a saponin or an aryl group, can be removed by, for example, hydrolysis, using a suitable test, such as a metal oxychloride, such as lithium hydroxide or sodium. Alternatively, an arylmethyl group, such as a benzyl group, can be removed by hydrogenation using, for example, a catalyst such as palladium on carbon. Suitable protecting groups for the carboxy group are, for example, esterifying groups, such as methyl hydrazine, which can be removed, for example by hydrolysis, using a base, such as sodium hydroxide, or, for example, a third-butyl group, It can be removed, for example, using an acid, such as an organic acid, such as trifluoroacetic acid, or, for example, a benzyl group, which can be removed, for example, by hydrogenation using a catalyst such as dry/carbon. The protecting group can be removed at any convenient stage in the synthesis using conventional techniques known in the art. The compound defined in the present invention as described above has anti-cell growth 120858 -49 - 200811169, such as anti-cancer activity, which is derived from the CDK inhibitory activity of the compound. These properties can be evaluated, for example using the procedure detailed below. - The following abbreviations have been used for the test: - HEPES is N-[2-hydroxyethyl]hexahydropyrazine-Nf-[2_ethanesulfonic acid] DTT is dithiothreitol PMSF is a phenylmethylfluorinated sulfonium compound tested in an in vitro kinase assay. In the 96 well format, scintillation proximity detection (SPA - from Amersham) was used to measure [r -33-P]·Incorporation of adenine triphosphate into the test substance (GST-retinal blastoma protein; GST-Rb). The compound to be tested (diluted in DMSO and water to correct the concentration) was placed in each well, and either roscovitine as an inhibitor control group or DMSO as a positive control group was placed in the control well. Approximately 0.2 μl of CDK2/cycline-purified partially purified enzyme (depending on enzyme activity) diluted in 25 μl of culture buffer was added to each well, followed by 20 μl of GST-Rb/ A mixture of ATP/ATP33 (containing 0.5 μg of GST_Rb with 0.2 //Μ ATP and 0.14 //Ci[ r-33-P]-adenine triphosphate in culture buffer), and the resulting mixture is gently shaken, It was then incubated at room temperature for 60 minutes.

接著，於各井中添加150微升終止溶液，其含有（0.8毫克/ 井之蛋白質A-PVT _SPA_??珠粒（Amersham))、20pM/井之抗-谷 胱甘肽轉移酶、兔子IgG (得自Molecular Probes)、61 mM EDTA 120858 -50- 200811169 及50 mM HEPES pH 7·5，含有0.05%疊氮化鈉。 將板以頂部密封-S板封閉器密封，留置兩小時，然後在 2500rpm，1124χ克下旋轉5分鐘。將板在頂部計數器上讀取， 每井30秒。 用以稀釋酵素與受質混合物之培養緩衝劑，含有50mM HEPES pH 7.5, 10mM MnCl2，ImM DTT，100 //Μ 釩酸鈉，100 //M NaF， 10mM甘油磷酸鈉，BSA (最後1毫克/毫升）。 試驗受質 在此項檢測中，僅使用部份視網膜胚細胞瘤蛋白質 (Science 1987 Mar 13 ； 235(4794) ： 1394-1399 ； Lee W.H., Bookstein R.5 Hong F·，Young L.J·，Shew J.Y·，Lee Ε·Υ·)，經融合至 GST 標記。進 行會使胺基酸379-928編碼之視網膜胚細胞瘤基因（得自視 網膜胚細胞瘤質粒ATCC pLRbRNL)之PCR，並使此順序無性 繁殖至 pGEx 2T 融合載體（Smith D.B.與 Johnson，K.S· Gene 67, 31 (1988);其含有供可誘發表現之tac啟動子，供使用於任何大 腸桿菌宿主之内部lac P基因，及供凝血酶***之密碼區域-得自Pharmacia Biotech)，其係用以放大胺基酸792-928。使此順 序再一次無性繁殖至pGEx2T中。 如此獲得之視網膜胚細胞瘤792-928順序，係使用標準可 誘發表現技術，表現於大腸桿菌（BL21 (DE3) pLysS細胞）中， 並按下述純化。 使大腸桿菌糊劑再懸浮於1〇毫升/克NETN緩衝劑（50mM Tris pH 7.5, 120mM NaCl，ImM EDTA，0·5%ν/ν NP-40, ImM PMSF，1 微克/毫升亮肽素，1微克/毫升抑肽酶及1微克/毫升胃蛋白 120858 -51 - 200811169 酶抑制素）中，並使每100毫升勻漿音振2 X 45秒。離心分離 後，將上層清液裝填至10毫升谷胱甘肽瓊脂糖管柱 (Pharmacia Biotech，Herts，UK)上，且以 NETN 緩衝劑洗條。在以 激酶緩衝劑（50mM HEPES pH 7.5，lOmM MgCl2，ImM DTT，ImM PMSF，1微克/毫升亮肽素，1微克/毫升抑肽酶及1微克/毫升 胃蛋白酶抑制素）洗滌後，將蛋白質以50 mM經還原谷胱甘 肽在激酶緩衝劑中溶離。將含有GST-Rb(792-927)之溶離份匯 集，並對著激酶緩衝劑滲析過夜。最後產物係藉由十二硫 酸納（SDS) PAGE (聚丙烯醢胺凝膠），使用8-16% Tris-甘胺酸凝 膠（Novex，San Diego, USA)分析。Next, 150 μl of stop solution containing 0.8 mg/well of protein A-PVT_SPA_?? beads (Amersham), 20 pM/well of anti-glutathione transferase, rabbit IgG (next) was added to each well. Available from Molecular Probes), 61 mM EDTA 120858 -50-200811169 and 50 mM HEPES pH 7.5, containing 0.05% sodium azide. The plate was sealed with a top seal-S plate sealer, left for two hours, and then spun at 2,500 rpm, 1124 gram for 5 minutes. The plate was read on the top counter for 30 seconds per well. A culture buffer for diluting the mixture of enzyme and substrate, containing 50 mM HEPES pH 7.5, 10 mM MnCl2, 1 mM DTT, 100 // 钒 sodium vanadate, 100 //M NaF, 10 mM sodium glycerophosphate, BSA (last 1 mg/ ML). Test Subjects In this assay, only partial retinoblastoma protein was used (Science 1987 Mar 13; 235 (4794): 1394-1399; Lee WH, Bookstein R.5 Hong F·, Young LJ·, Shew JY ·, Lee Ε·Υ·), fused to the GST mark. PCR was performed on the retinoblastoma gene (derived from retinoblastoma plasmid ATCC pLRbRNL) encoding amino acid 379-928, and this sequence was vegetatively propagated to the pGEx 2T fusion vector (Smith DB and Johnson, KS· Gene 67, 31 (1988); it contains a tac promoter for inducible expression for use in the internal lac P gene of any E. coli host, and a cryptodomain for thrombin division - from Pharmacia Biotech) To amplify the amino acid 792-928. This sequence was once asexually propagated into pGEx2T. The retinoblastoma 792-928 sequence thus obtained was expressed in Escherichia coli (BL21 (DE3) pLysS cells) using standard inducible expression techniques and purified as follows. The E. coli paste was resuspended in 1 mL/g NETN buffer (50 mM Tris pH 7.5, 120 mM NaCl, 1 mM EDTA, 0.5% ν/ν NP-40, 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and 1 μg/ml pepsin 120858-51 - 200811169 enzymatic statin), and homogenize each 100 ml homogenate for 2 x 45 seconds. After centrifugation, the supernatant was loaded onto a 10 ml glutathione agarose column (Pharmacia Biotech, Herts, UK) and washed with NETN buffer. Protein was washed after washing with kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM DTT, 1 mM PMSF, 1 μg/ml leupeptin, 1 μg/ml aprotinin and 1 μg/ml pepstatin) The reduced glutathione was dissolved in kinase buffer at 50 mM. The fractions containing GST-Rb (792-927) were pooled and dialyzed against the kinase buffer overnight. The final product was analyzed by sodium dodecyl sulfate (SDS) PAGE (polyacrylamide gel) using 8-16% Tris-glycinate gel (Novex, San Diego, USA).

CDK2與環素E CDK2與環素E之開放譯讀骨架係藉由反轉錄酶-PCR單 離，使用HeLa細胞與經活化之T細胞mRNA作為模板，且無 性繁殖至昆蟲表現載體PVL1393 (得自Invitrogen 1995目錄編 號：V1392-20)。然後，使CDK2與環素E雙重表現[使用標準 病毒Baculogold共感染技術]於昆蟲SF21細胞系統（衍生自秋 夜蛾卵巢組織之草地黏蟲（Spodoptera Frugiperda)細胞-市購可 得）。 製造環素E/CDK2之實例 下述實例係提供在SF21細胞中（在TC100 + 10% FBS(TCS) + 0.2% Plunmic)，製造環素E/CDK2之細節，對環素& CDK2之各 病毒具有雙重感染MOI 3。 將在滚筒瓶培養物中生長至2·33 X 106個細胞/毫升之SF21 細胞，用以接種10 X 500毫升滾筒瓶，在0·2 X 10E6個細胞/ 120858 -52- 200811169 毫升下。使滚筒瓶在滾筒機床上，於28°C下培養。 3天（72小時）後，將細胞計數，而得自2個瓶子之平均， 發現係為1.86 X 10E6個細胞/毫升（99%存活）。然後，將培養 物以雙病毒感染，對各病毒在MOI 3下。 在添加至培養物中之前，將病毒混合在一起，並使培養 物返回28°C之滾筒機床。 於2天（48小時）後感染之後，採集5升培養物。於採集下 之總細胞計數為1.58 X 10E6個細胞/毫升（99%存活）。使細胞 在 2500rpm，30分鐘，4°C，在 Heraeus OmnifUge 2.0 RS 中，以 250 毫升批料旋轉出來。拋棄上層清液。 CDK2與環素E之部份共純化 使Sf21細胞再懸浮於溶胞緩衝劑（50mM Tris pH 8.2，10mM MgCl2，ImM DTT，10mM甘油磷酸酯，（UmM 正釩酸鈉，O.lmM NaF，ImM PMSF，1微克/毫升亮肽素及1微克/毫升抑肽酶） 中，且在10毫升Dounce均化器中均化2分鐘。於離心分離 後，將上層清液裝填至Poros HQ/M 1.4/100陰離子交換管柱(PE Biosystems，Hertford，UK)上。使CDK2與環素E共溶離，在開始 時為0-1M NaCl梯度液（在減去蛋白酶抑制劑之溶胞緩衝劑 中操作），歷經20個管柱體積。共溶離係藉由Western氏沾吸 檢查’使用抗-CDK2與抗_環素E兩種抗體（Santa Cruz生物技 術，California，US)。 藉由類似方式，可建構經設計以評估CDK1與CDK4抑制之 檢測。CDK2 (EMBL收受號碼X62〇71)可與環素A或環素E(參 閱EMBL收受號碼M73812) —起使用，而關於此種檢測之進一 120858 -53 - 200811169 步細節係被包含在PCT國際公報W099/21845中，其中有關聯 之生物化學與生物學評估段落均據此併於本文供參考。 雖然式（I)化合物之藥理學性質會隨著結構變化而改變， 但一般而言，式（I)化合物所具有之活性，可在25〇 _至丨 範圍内之IC5 0濃度或劑量下《I正實。 當在上述活體外檢測中測試時，實例29之CDK2抑制活性 係經度量為IC5〇= 95 nM。 根據本發明之進一步方面，係提供一種醫藥組合物，其 包含如前文定義之式（I)嘧啶衍生物，或其藥學上可接受之 鹽或活體内可水解酯，伴隨著藥學上可接受之稀釋劑或載 劑。 組合物可呈適當形式，例如作成片劑或膠囊供口服投 藥，作成無菌溶液、懸浮液或乳化液供非經腸注射（包括靜 脈内、皮下、肌内、血管内或灌注），作成軟f或乳膏供局 部投藥’或作成栓劑供直腸投藥。 k而口上述組合物可以習用方式，使用習用賦形劑 製備。 式(I)化a物通吊係在每平方米動物身體面積彻〇毫克 範圍内之單位劑量下，投予溫血動物，意即大約〇鳩毫 克/么斤’且其通常係提供治療上有效劑量。單位劑型，座 如片劑或膠囊，通常含有例如㈣毫克活性成份。較㈣ 抓用1-50¾克/公斤範圍内之日服劑量。但是，日服劑量將 必須依待治療之宿主、特定投藥途徑及被治療疾病之嚴重 性而改k。因此，最適宜劑量可由正在治療任何特定病患 120858 -54- 200811169 之執業醫師決定。 根據本發明之進一步方面，係提供如前文定義之式(1)化 σ物或其藥學上可接受之鹽或活體内可水解g旨，供使用於 藉由療法以治療人類或動物身體之方法中。 吾人已發現，於本發明中定義之化合物或其藥學上可接 受之鹽或活體内可水解酯，係為有效細胞循環抑制劑（抗細 胞增生劑），咸信此性質係源自於其CDK抑制性質。因此， 預期本發明化合物可用於治療單獨或部份藉由CDK酵素所 媒介之疾病或醫療症狀，意即此等化合物可在需要此種治 療之溫血動物中，用以產生CDK抑制作用。因此，本發明 化合物係提供一種治療惡性細胞增生之方法，其特徵為抑 制CDK酵素，意即此等化合物可用以產生單獨或部份藉由 CDK之抑制所媒介之抗增生與潛在地細胞凋零作用。特定 言之，抑制作用係藉由抑制CDK2、CDK4及/或CDK6，尤其 是CDK2，預防其進入或進展經過s期，及藉由抑制CDKi進 入或進展經過Μ期而產生。亦可設想到細胞凋零作用係經 過RNA聚合酶Π活性之向下調節，其方式是抑制CDKi、 CDK7 ' CDK8，且特別是CDK9。預期本發明之此種化合物 具有廣範圍之抗癌性質，因CDK係與許多一般人類癌症有 關聯，譬如白血病，及***、肺臟、結腸、直腸、胃、前 列腺、膀胱、胰臟及卵巢癌。因此，預期本發明化合物將 具有抵抗此等癌症之抗癌活性。此外，預期本發明化合物 將具有抵抗一範圍之白血病、淋巴樣惡性病症及固態腫 瘤，譬如在一些組織例如肝臟、腎臟、***及胰臟中之 120858 -55- 200811169 癌瘤與肉瘤之活性。特定言之，預期本發明之此種化合物 可有利地減緩例如結腸、***、***、肺臟及皮膚之原 發性與再發生固態腫瘤之生長。更特定言之，預期本發明 之此種化合物或其藥學上可接受之鹽或活體内可水解醋， 會抑制與cm㈣聯^純與再發生㈣㈣之生長， 尤其是顯著地依賴CDK之腫瘤，關於其生長與擴展，包括 例如結腸、***、***、肺臟、女陰及皮膚之某些腫瘤。 進-步預期本發明化合物將在廣範圍其他疾病狀態中具 有抵抗其他細胞增生疾病之活性，該疾病包括白企病、纖 維增生，分化病症、牛皮癬、風濕性關節炎、卡波西氏肉 瘤血g瘤、急性與慢性腎病、動脈粥瘤、動脈粥瘤硬化、 動脈再狹窄、自身免疫疾病、急性與慢性發炎、骨質疾病 及具有視網膜血管增生之眼部疾病。 因此’根據本發明之此方面，係提供如前文定義之式① 化口物’或其藥學上可接受之鹽或活體内可水解醋，作為 藥劑使用。 於本發明之進一步方面，彳έ if* Wit 和 万面係如供如丽文定義之式（I)化合 物或其藥學j可接受之鹽或活體内可水解酉旨於藥劑製造上 之用途，该藥劑係用於產生細胞循環抑制作用。 於本發明之-方面，在指稱細胞循環抑制作用之情況下， 此係指CDK i之抑制。於本發明之進一步方面，此係指⑽ 之抑制。於本發明之進—步方面’此係指CDK4之抑制。於 本發明之進-步方面’此係指·之抑制。於本發明之進 一步方面’此係指CDK6之抑制。於本發明之進一步方面， 120858 -56- 200811169 此係指CDK7之抑制。於本發明之進一步方面，此係指cdk8 之抑制。於本發明之進一步方面，此係指CDK9之抑制。 於本發明之進一步方面，係提供如前文定義之式⑺化合 物或其藥學上可接受之鹽或活體内可水解醋於藥劑製造上 之用返，该藥劑係用於產生抗細胞增生作用。 於本^月之進一步方面，係提供如前文定義之式（I)化合 物或其藥學上可接受之鹽或活體内可水解醋於藥劑製造上 之用途，該藥劑係用於產生CDK2抑制作用。 於本，明之進—步方面，係提供如前文定義之式（I)化合 物或其藥學上可接受之鹽或活體内可水解_於藥劑製造上 之用途，該藥劑係用於治療癌症。 於本：明之進-步方面，係提供如前文定義之式(I)化合 物或其藥學上可接受之鹽或活體内可水解酯於藥劑製造上 之用途1¾藥劑係用於治療白血病或淋巴樣惡性病症，或 ***、肺臟、結腸、直腸、胃、肝臟、腎臟、***、膀 胱、胰臟、女陰、皮膚或印巢之癌症。 根據本發明之進—+胜外 r 、 <進步特被，係提供如前文定義之式①化 合物或其藥學上可接受之鹽或活體内可水解醋於藥劑製造 上之用途4藥劑仙於治療癌症、纖維增生與分化病症、 牛皮癖、風濕性關節炎、卡波西氏肉冑、血管瘤、急性血 慢性月病、動脈粥瘤、動脈粥瘤硬化、動脈再狹窄、自身 免疫疾病、急性與慢性發炎 管增生之眼部疾病。…病及伴隨著視網膜血 於本發明之進_ 步方面，係提供一 種在需要治療之溫血CDK2 and Cyclin E CDK2 and Cyclin E are open-reading backbones by reverse transcriptase-PCR, using HeLa cells and activated T cell mRNA as templates, and asexually propagated to the insect expression vector PVL1393 (obtained) From Invitrogen 1995 catalog number: V1392-20). Then, CDK2 and cyclin E were double-expressed [using the standard virus Baculogold co-infection technique] in the insect SF21 cell system (derived from Spodoptera Frugiperda cells - commercially available). Examples of the production of cyclin E/CDK2 The following examples are provided in SF21 cells (at TC100 + 10% FBS (TCS) + 0.2% Plunmic) to produce details of cyclin E/CDK2, for each of cyclin & CDK2 The virus has a dual infection with MOI 3. SF21 cells grown to 2·33 X 106 cells/ml in roller flask cultures were used to inoculate 10 X 500 ml roller bottles at 0·2 X 10E6 cells/120858-52-200811169 ml. The roller bottle was incubated on a roller machine at 28 °C. After 3 days (72 hours), the cells were counted and averaged from 2 bottles and found to be 1.86 X 10E6 cells/ml (99% viable). Then, the culture was infected with a double virus, and each virus was subjected to MOI 3. Prior to addition to the culture, the viruses were mixed together and the culture returned to a roller machine at 28 °C. After infection after 2 days (48 hours), 5 liters of culture were collected. The total cell count under acquisition was 1.58 X 10E6 cells/ml (99% viable). The cells were spun out at 2500 rpm, 30 min, 4 °C in a Heraeus OmnifUge 2.0 RS in 250 ml batch. Discard the supernatant. Co-purification of CDK2 with a portion of Cyclin E to resuspend Sf21 cells in lysis buffer (50 mM Tris pH 8.2, 10 mM MgCl2, 1 mM DTT, 10 mM glycerophosphate, (UmM sodium orthovanadate, O.lmM NaF, 1 mM) PMSF, 1 μg/ml leupeptin and 1 μg/ml aprotinin) and homogenized for 2 minutes in a 10 ml Dounce homogenizer. After centrifugation, the supernatant was filled to Poros HQ/M 1.4 /100 anion exchange column (PE Biosystems, Hertford, UK). Co-dissolve CDK2 with cyclin E, starting with a 0-1 M NaCl gradient (operating in a lysis buffer with a protease inhibitor minus) After 20 column volumes, the co-dissolved line was examined by Western blotting using 'anti-CDK2 and anti-cycline E antibodies (Santa Cruz Biotechnology, California, US). Designed to assess the detection of CDK1 and CDK4 inhibition. CDK2 (EMBL acceptance number X62〇71) can be used with cyclin A or cyclin E (see EMBL acceptance number M73812), and for this test, further into 120858-53 - 200811169 Step details are included in PCT International Gazette W099/21845, where relevant The biochemical and biological evaluation paragraphs are hereby incorporated by reference. Although the pharmacological properties of the compounds of formula (I) vary with structural changes, in general, the compounds of formula (I) have activity The CDK2 inhibitory activity of Example 29 can be measured as IC5 〇 = 95 nM when tested in the above in vitro assay when tested at the IC50 concentration or dose in the range of 25 Å to 丨. In a further aspect, there is provided a pharmaceutical composition comprising a pyrimidine derivative of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, accompanied by a pharmaceutically acceptable diluent or The composition may be in a suitable form, for example, as a tablet or capsule for oral administration, as a sterile solution, suspension or emulsion for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or perfusion), Prepare a soft f or cream for topical administration or as a suppository for rectal administration. k The above composition can be prepared in a conventional manner using conventional excipients. A unit dose of the body is administered at a unit dose within the range of milligrams, which is administered to a warm-blooded animal, which means approximately 〇鸠mg/kg 斤' and usually provides a therapeutically effective dose. Unit dosage form, such as a tablet or capsule, usually Contains, for example, (four) mg of active ingredient. (4) The daily dose in the range of 1-503⁄4 g/kg. However, the daily dose will have to be changed depending on the host to be treated, the specific route of administration, and the severity of the disease being treated. . Therefore, the optimal dose can be determined by the practitioner who is treating any particular patient 120858-54-200811169. According to a further aspect of the present invention, there is provided a method of treating a human or animal body by therapy, wherein the sigma compound of the formula (1), or a pharmaceutically acceptable salt thereof, or the in vivo hydrolysable g, is as defined above. in. It has been found that a compound as defined in the present invention, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, is an effective cell cycle inhibitor (anti-cell proliferator), which is derived from its CDK. Inhibition properties. Thus, the compounds of the invention are expected to be useful in the treatment of a disease or medical condition, mediated alone or in part by CDK enzymes, meaning that such compounds can be used to produce CDK inhibition in warm-blooded animals in need of such treatment. Thus, the compounds of the present invention provide a method of treating malignant cell proliferation characterized by inhibition of CDK enzymes, meaning that such compounds can be used to produce anti-proliferative and potentially cellular defensive effects, either alone or in part by inhibition of CDK. . In particular, inhibition is achieved by inhibiting CDK2, CDK4 and/or CDK6, particularly CDK2, from entry or progression through the s phase, and by inhibiting CDKi entry or progression through the sputum. It is also conceivable that the cell dying effect is down-regulated by RNA polymerase activity by inhibiting CDKi, CDK7 'CDK8, and especially CDK9. Such compounds of the present invention are expected to have a wide range of anti-cancer properties, as the CDK line is associated with many common human cancers, such as leukemia, and breast, lung, colon, rectum, stomach, prostate, bladder, pancreas, and ovarian cancer. Thus, it is expected that the compounds of the invention will have anti-cancer activity against these cancers. Furthermore, it is expected that the compounds of the invention will be resistant to a range of leukemias, lymphoid malignancies and solid tumors, such as 120858-55-200811169 cancer and sarcoma activity in some tissues such as liver, kidney, prostate and pancreas. In particular, it is contemplated that such compounds of the invention may advantageously slow the growth of, for example, the colon, breast, prostate, lung and skin primary and re-solid tumors. More specifically, it is expected that the compound of the present invention, or a pharmaceutically acceptable salt thereof or a hydrolyzable vinegar in vivo, inhibits the growth of (c) and recurrence (c) (iv), especially a tumor which is significantly dependent on CDK, Regarding its growth and expansion, including certain tumors such as the colon, breast, prostate, lung, female genital and skin. Further, it is expected that the compounds of the present invention will have activity against other cell proliferative diseases in a wide range of other disease states including white disease, fibrosis, differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma blood. g tumor, acute and chronic kidney disease, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, bone disease and ocular disease with retinal vascular proliferation. Thus, according to this aspect of the invention, a mouthwash of the formula 1 as defined above or a pharmaceutically acceptable salt thereof or a hydrolyzable vinegar in vivo is used as a medicament. In a further aspect of the invention, 彳έ if* Wit and ubiquitin are for use in the manufacture of a medicament, for example, a compound of formula (I) as defined by Lie, or a pharmaceutically acceptable salt thereof or a hydrolyzable substance in vivo, This agent is used to produce cell cycle inhibition. In the aspect of the present invention, in the case of referring to inhibition of cell cycle, this means inhibition of CDK i . In a further aspect of the invention, this refers to the inhibition of (10). In the context of the present invention, this refers to the inhibition of CDK4. In the further aspect of the invention, this refers to the inhibition of the invention. In a further aspect of the invention, this refers to inhibition of CDK6. In a further aspect of the invention, 120858-56-200811169 this refers to inhibition of CDK7. In a further aspect of the invention, this refers to inhibition of cdk8. In a further aspect of the invention, this refers to inhibition of CDK9. In a further aspect of the invention there is provided a compound of formula (7), or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable vinegar, as defined above, for use in the manufacture of a medicament for the production of an anti-cell proliferative effect. In a further aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable vinegar, as defined above, for the manufacture of a medicament for the production of CDK2 inhibition. In the context of the present invention, there is provided a use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a hydrolyzable in vivo, as defined above, for the treatment of cancer. In the present invention, the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, as defined above, for the manufacture of a medicament is provided for the treatment of leukemia or lymphoid A malignant condition, or a cancer of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, genital, skin, or nest. According to the present invention, the invention provides a compound of the formula 1 as defined above, or a pharmaceutically acceptable salt thereof or a hydrolyzable vinegar in vivo for use in the manufacture of a medicament. Treatment of cancer, fibrosis and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's meat emulsion, hemangioma, acute chronic blood disease, atheroma, atherosclerosis, arterial restenosis, autoimmune diseases, Eye diseases of acute and chronic inflammatory tube hyperplasia. ... disease and accompanying retinal blood in the advancement of the present invention, providing a warm blood in need of treatment

120S5S -57- 200811169 動物中產生細胞循環抑制作用之方法，其包括對該動物投 予有效量之如前文定義之式（I)化合物或其藥學上可接受之 鹽或活體内可水解酯。 於本發明之進一步方面，係提供一種在需要治療之溫血 動物中產生抗細胞增生作用之方法，其包括對該動物投予 有效量之如前文定義之式（I)化合物或其藥學上可接受之鹽 或活體内可水解酯。 於本發明之進一步方面，係提供一種在需要治療之溫血 動物中產生CDK2抑制作用之方法，其包括對該動物投予有 效I之如如文定義之式（j)化合物或其藥學上可接受之鹽或 活體内可水解酯。 於本發明之進一步方面，係提供一種在需要治療之溫血 動物中治療癌症之方法，其包括對該動物投予有效量之如 月J文义義之式（I)化合物或其藥學上可接受之鹽或活體内可 水解S旨。120S5S -57- 200811169 A method of producing cell cycle inhibition in an animal comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinbefore defined. In a further aspect of the invention, there is provided a method of producing an anti-cell proliferative effect in a warm-blooded animal in need of treatment comprising administering to the animal an effective amount of a compound of formula (I) as hereinbefore defined or a pharmaceutically acceptable Accepted salts or hydrolyzable esters in vivo. In a further aspect of the invention, there is provided a method of producing a CDK2 inhibitory effect in a warm-blooded animal in need thereof, comprising administering to the animal an effective I, a compound of formula (j) as defined herein, or a pharmaceutically acceptable Accepted salts or hydrolyzable esters in vivo. In a further aspect of the invention, there is provided a method of treating cancer in a warm-blooded animal in need of treatment comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable compound thereof, as defined herein Salt or in vivo hydrolyzable.

係提供一種在需要治療之溫血Provides a warm blood in need of treatment

於本發明之進一步方面， 動物中治療癌症 關節炎、卡波西f 120858 -58- 200811169 粥瘤、動脈粥瘤硬化、動脈再狹窄、自身免疫疾病、急性 與r又欧Ii、骨質疾病及伴隨著視網膜血管增生之眼部疾 〉丙方法其包括對該動物投予有效量之如前文定義之式 (1)化合物或其藥學上可接受之鹽或活體内可水解醋。 入於j發明之進一步方面，係提供一種醫藥組合物，其包 j文疋義之式（I)化合物或其藥學上可接受之鹽或活體 内可水解i旨，與藥學上可接受之稀釋劑或載劑。 人於本發明之進一步方面，係提供一種醫藥組合物，其包 各如刖文疋義之式①化合物或其藥學上可接受之鹽或活體 内可水解_，㈣學上可接受之稀釋劑或載劑，作為藥劑 使用。 於本發明之進_步方面，係提供—種醫藥組合物，其包 含如前文定義之式(1)化合物或其藥學上可接受之鹽或活體 内可水解㉙，肖藥學上可接受之稀釋H載劑，用於產生 細胞循環抑制作用。 月之進一步方面，係提供一種醫藥組合物，其包 “刖文定義之式(1)化合物或其藥學上可接受之鹽或活體 内可Jc解酉日，肖藥學上可接受之稀釋劑或載劑，用於產生 抗細胞增生作用。 人於=發：之進一步方面，係提供一種醫藥組合物，其包 a如别文定義之式(1)化合物或其藥學上可接受之鹽或活體In a further aspect of the invention, the treatment of cancer arthritis in animals, Kaposi f 120858-58-200811169 atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and r-Eu Ii, bone disease and accompanying Eye disease of retinal vascular hyperplasia > The method comprises administering to the animal an effective amount of a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable vinegar. In a further aspect of the invention of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof or a hydrolyzable substance in vivo, together with a pharmaceutically acceptable diluent Or carrier. In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula 1 as hereinbefore or a pharmaceutically acceptable salt thereof or a hydrolyzable in vivo, (4) a scientifically acceptable diluent or The carrier is used as a medicament. In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (1), or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable, as defined hereinbefore, in a pharmaceutically acceptable dilution H carrier for the production of cell cycle inhibition. In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable diluent or A carrier for the production of an anti-cell proliferative effect. In a further aspect, the invention provides a pharmaceutical composition comprising a compound of the formula (1) as defined herein, or a pharmaceutically acceptable salt or living body thereof

内可水解_，肖藥學上可接受之稀釋劑或載劑，用於產生 CDK2抑制作用。 I 於本發明之推_半 y 面’係提供一種醫藥組合物，其包 120858 -59- 200811169 含如前文定義之式（I)化合物或其藥學上可接受之鹽或活體 内可水解酯，與藥學上可接受之稀釋劑或载劑，用於治療 癌症。 -於本發明之進一步方面，係提供一種醫藥組合物，其包 含如前文定義之式①化合物或其藥學上可接受之鹽或：體 内可水解i旨，肖藥學上可接受之稀釋劑或载劑，用於治療 白血病或淋巴樣惡性病症或***、肺臟、結腸、直腸、胃、 肝臟、腎臟、***、膀胱、胰臟、女陰、皮膚或卵巢之 癌症。 於本發明之進一步方面，係提供一種醫藥組合物，其包 3七文疋義之式①化合物或其藥學上可接受之鹽或活體 内可水解酿，肖藥學上可接受之稀釋劑或載劑，用於治療 癌症、纖、、隹増生與分化病症、牛皮癖、風濕性關節炎、卡 波西氏肉瘤、也管瘤、急性與慢性腎病、動脈粥瘤、動脈 粥瘤硬化、動脈再狹窄、自身免疫疾病、急性與慢性發炎、 骨質疾病及伴隨著視網膜血管增生之眼部疾病。 於本叙明之進-步方面，係提供如前文定義之式(I)化合 物或其藥學上可接受之鹽或活體内可水解_於產生細胞循 環抑制作用上之用途。 於本，明之進_步方面，係提供如前文定義之式⑺化合 物或其藥學上可接受之鹽或活體内可水解酷於產生抗細胞 增生作用上之用途。 j本U之進一步方面，係提供如前文定義之式①化合 〆八某予上可接受之鹽或活體内可水解酯於產生Cdk2 120858 -60- 200811169 抑制作用上之用途。 於本發明之彳隹—丰 進 乂方面，係提供如前文定義之式（I)化合 物或其藥學上可垃g . 接又之鹽或活體内可水解酯於治療癌症上 之用途。 於本，明之進一步方面，係提供如前文定義之式（I)化合 物H予上可接受之鹽或活體内可水解_於治療白血病 =淋巴=惡性病症或***、肺臟、結腸、直腸、胃、肝臟、 、、月j歹J腺膀胱 '胰臟、女陰、皮膚或印巢癌症上之 用途。 根據本發明之進—步特徵，係提供如前文定義之式①化 合物或其藥學上可接受之鹽或活體内可水解S旨於治療癌 症纖維&生與分化病症、牛皮癖、風濕性關節炎、卡波 西氏肉瘤、血管瘤、急性與慢性腎病、動脈粥瘤、動脈粥 瘤更化冑脈再狹窄、自身免疫疾病、急性與慢性發炎、 骨^疾病及伴隨著視網膜血管增生之眼部疾病上之用途。 藉由抑制引發活性所必須之8_期，譬如CDK2引發作用， 以防止細胞進人眶合成中，亦可用於保護㈣之正常細 胞’免於循環專一藥劑之毒性。CDK2或4之抑制，將防止 進展至正常細胞之細胞循環中，其可限制會作用在&期、 G2或有絲***中之循環專—藥劑之毒性。此種保護可造成 防止通常與此等藥劑有關聯之毛髮掉落。 因此’於本發明之另—方面，係、提供如上文定義之式① 化合物或其藥學上可接受之鹽或活體内 胞保護劑使用。 乍為、 120858 -61 - 200811169 因此，於本發明之進一步方面，係提供如上文定義之式 (I)化合物或其藥學上可接受之鹽或活體内可水解酯，用於 防止由於使用藥劑治療惡性症狀而發生之毛髮掉落。 用於治療惡性症狀而已知會造成毛髮掉落之藥劑之實 例，包括烷基化劑，譬如依發斯醯胺（ifosfamide)與環磷醯胺； 抗代謝物’譬如胺曱喋呤、5_氟尿嘧啶、真西塔賓(gem—bine) 及阿糖胞甞；長春花植物鹼及類似物，譬如長春新鹼、長 春花鹼、長春花素、威諾賓（vin〇relbine);紅豆杉烷類，譬如 培克里他t (paditaxel)與乡謝他t (d。咖d) ; #㈣構酶ι抑 制劑，譬如伊林托提肯(H齡ean)與拓波提肯㈣；細 胞毒性抗生素，譬如多克索紅菌素、道諾紅菌h絲裂黃 酮（mit〇Xantr〇ne)、放線菌素-D及絲裂霉素，·及其他，譬如衣 托糖芬（etoposide)與崔替諾因（tretin〇in)。 贫物，或其市于丄1筏文 =或Γ體内可水解8旨，可伴隨著—或多種上述藥劑一起 情況中，式①化合物可藉由系統或非系統方式 如局部投藥。 猎由非錢方式投藥，例 q凡’隹本發明之另一瑁 劑户疼.^ ^ 、寺铽中，係提供一種於使用藥 I療-或多種惡性症狀期 防止革影妯β 4 + 勒物言如人類中， :毛！掉洛之方法，其包括對該 化合物，或其藥學上可接 Τ有效里之式① 於本發明之另-項特伐中或活體内可水解醋。 ，《性症狀期間，在溫藥劑治療 剪物言如人類中，防止毛 120858 -62- 200811169 髮掉落之方法，其包括對該動物投予有效量之式①化合 物，或其藥學上可接受之鹽或活體内可水解醋，且同時、 相繼或個別投予有效量之該藥劑。 根據本發明之另一方面 系—種醫藥組合物，用於 防止由於使用藥劑治療亞降 ⑷。欲μ〖生症狀而發生之毛髮掉落，苴包 含式①化合物，或其藥學上可接受之鹽或活體内可水解：， 且該藥劑係伴隨著藥學上可接受之稀釋劑或載劑。 根據本發明之另一方面，筏担 面係提供一種套件，其包含式（I) 化合物，或其藥學上可接# 又之孤或，舌體内可水解S旨，及用 以治療惡性症狀而已知會造成毛髮掉落之藥劑。 根據本發明之另一方面，筏担 m 係如供一種套件，其包含： a) 式（I)化合物，或其攀學 a 、/、 上了接文之鹽或活體内可水解酯， 呈第一種單位劑量形式； b) 用於治療惡性症狀而已知合、皮 匕失曰造成毛髮掉落之藥劑；呈第 二種單位劑量形式；及 c) 用於合肩該第一種與第二種劑量形式之容器裝置。 根據本發明之另一特徵’係提供式①化合物，或其藥學 上可接文之鹽或活體内死士 円了水解醋於藥劑製造上之用途，該 藥劑係在使用藥劑治瘠亞柯 康心性症狀期間，用於防止毛髮掉落。 “根據本發明之進一步方面’係提供一種用於防止毛髮掉 落之 '且口 ’口療其包括對溫血動物譬如人類，投予有效量 之式①化合物或其藥學上可接受之鹽或活體内可水解醋， 視情況伴隨著藥學上可接a + μ γ 、 j接又之稀釋劑或載劑，且同時、相 或個別投予有效量之用私 里之用於治療惡性症狀之藥劑。 120858 -63- 200811169 如上文所述’用於治療或預防治療特定細胞增生疾病所 而要剡里之大小，係必須依待治療之宿主、投藥途徑及被 治療疾病之嚴重性而改變。單位劑量，在例如剛毫克/ 公斤之耽圍内，較佳為毫克/公斤，是可設想到的。 前文定義之CDK抑制活性，可以單—療法施用，或除了 本發明化合物之外，可涉及一或多種其他物質及/或治療。 此種共同治療可經由同日夺、相繼或個別投予治療之個別成 份而達成。在醫療腫瘤學之領域中，丨常實施係使用不同 治療形式之組合，以治療每位具有癌症之病患。在醫療腫 瘤學中’此種共同治療之其他成份，&了前文所^義之細 胞循環抑制治療以外’可為：手術、射線療法或化學療法。 此種化學療法可涵蓋二種主要治療劑類別： ①其他細胞循環抑制劑，藉由與前文所定義者相同或不 同之機制發生作用； ⑼細胞抑制劑，譬如抗***（例如他摩西吩(tam〇xifen)、 托里米吩（t〇remifene)、瑞洛西吩（ral〇xifene)、卓洛西吩 (dr〇l〇xifene)、碘氧吩（iod〇xyfene))、孕激素類（例如甲地孕酮醋 酸鹽）、芳香酶抑制劑（例如安那史唑（anastr〇z〇le)、列措唑 (letrazole)、玻拉唑（vorazde)、約克美斯烷（找細防加切、抗孕 激素類、抗雄激素物質（例如弗如醯胺（flutamide)、尼如醯胺 (mlutamide)、二卡如醯胺（bicalutamide)、環丙氯地孕g同醋酸蹿）、 LHRH催動劑與拮抗劑（例如郭捨瑞林（g〇sereHn)醋酸鹽、留普 洛賴得（Luprolide))、睪酮5 α -二氫還原酶之抑制劑（例如菲那 史替來（finasteride))、抗侵入劑（例如金屬蛋白酶抑制劑，例 120858 -64 - 200811169 如馬利制酶素（Marimastat)，與尿激酶血纖維蛋白溶酶原活化 劑受體功能之抑制劑）及生長因子功能之抑制劑（此種生長 因子包括例如血小板衍生之生長因子與肝細胞生長因子， 此種抑制劑包括生長因子抗體、生長因子受體抗體、酪胺 酸激酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑）；及 (iii)使用於醫療腫瘤學之抗增生/抗腫瘤藥物及其組合，鐾 如抗代謝物（例如抗葉酸鹽，例如胺甲喋呤，氟基嘧啶類， 例如5-氟尿嘧啶，嘌呤及腺：y：類似物，***糖胞誓）；抗 腫瘤抗生素（例如蒽環素，例如多克索紅菌素、道諾霉素、 表紅菌素與依達紅菌素、絲裂霉素_c、達克汀霉素、光神 霉素）；鉑衍生物（例如順氯胺鉑、碳氯胺鉑”烷基化劑（例 如氮芥、***酸氮芥、苯丁酸氮芥（chl〇rambudl)、白血福 恩（busulphan)、環磷醯胺、依發斯醯胺（if〇sfamide)、亞硝基脲Y 嘧替哌（thiotepa));抗有絲***劑（例如長春花植物，例如長 春新鹼，與類紅豆杉物質，例如紅豆杉醇、紅豆杉帖里 (taX〇tere));拓樸異構酶抑制劑（例如表鬼臼脂素，例如衣托 糠苷（etoposide)與天尼荅，阿姆薩素（amsacrine)，拓波^肯 (t〇P〇teCan))。根據本發明之此方面，係提供一種醫藥產物^ 其包含如則文定義之式（1)化合物’及另一種如前文定義之 抗腫瘤物貝，用於癌症之共同治療。Internally hydrolyzable, a pharmaceutically acceptable diluent or carrier for the production of CDK2 inhibition. I, in the present invention, provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as defined above, 120858-59-200811169, And a pharmaceutically acceptable diluent or carrier for the treatment of cancer. - In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula 1 as hereinbefore defined, or a pharmaceutically acceptable salt thereof, or in vivo hydrolyzable, pharmaceutically acceptable diluent or A carrier for the treatment of leukemia or lymphoid malignancy or cancer of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, genital, skin or ovary. In a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof or a hydrolyzable in vivo, pharmaceutically acceptable diluent or carrier For the treatment of cancer, fibrosis, twins and differentiation disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, angiogenesis, acute and chronic kidney disease, atherosclerosis, atherosclerosis, arterial restenosis , autoimmune diseases, acute and chronic inflammation, bone diseases and eye diseases associated with retinal vascular proliferation. In the further aspect of the present invention, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or in vivo hydrolyzable, as defined above, for the production of a cell cycle inhibitory effect is provided. In the present invention, the use of the compound of the formula (7) as defined above or a pharmaceutically acceptable salt thereof or the in vivo hydrolysis of the compound for the purpose of producing an anti-cell proliferative effect is provided. Further aspects of the present invention provide the use of a compound of formula 1 as defined above, an acceptable salt or an in vivo hydrolysable ester for the inhibition of Cdk2 120858-60-200811169. In the aspect of the present invention, the use of a compound of the formula (I) as defined above or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo for the treatment of cancer is provided. In a further aspect of the present invention, the compound H of the formula (I) as defined above is provided as an acceptable salt or hydrolyzable in vivo - in the treatment of leukemia = lymphatic = malignant condition or breast, lung, colon, rectum, stomach, The use of the liver, the liver, the moon, the glandular bladder, the pancreas, the female genital, the skin, or the nest cancer. According to a further feature of the invention, there is provided a compound of formula 1 as hereinbefore defined, or a pharmaceutically acceptable salt thereof or in vivo hydrolysable S, for the treatment of cancer fibers & birth and differentiation disorders, psoriasis, rheumatoid joints Inflammation, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, atheroma, venous restenosis, autoimmune disease, acute and chronic inflammation, bone disease and eye with retinal vascular hyperplasia The use of the disease. By inhibiting the 8_ phase necessary for initiating the activity, such as CDK2 priming, to prevent cells from entering the sputum synthesis, it can also be used to protect the normal cells of (4) from the toxicity of the circulating specific agent. Inhibition of CDK2 or 4 will prevent progression to the cell cycle of normal cells, which may limit the toxicity of circulating specific agents that will act in &, G2 or mitosis. This protection can result in the prevention of hair loss that is normally associated with such agents. Thus, in a further aspect of the invention, there is provided a compound of formula 1 as defined above, or a pharmaceutically acceptable salt thereof or a cytoprotective agent for use in vivo.乍, 120858-61 - 200811169 Accordingly, in a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as hereinbefore defined, for use in the treatment of a medicament for treatment Hair that occurs with malignant symptoms falls. Examples of agents known to cause malignant symptoms and which are known to cause hair loss, include alkylating agents such as ifosfamide and cyclophosphamide; antimetabolites such as amine oxime, 5-fluorouracil , gem-bine and arabinose; vinca alkaloids and analogues, such as vincristine, vinblastine, vinca, vin〇relbine; catechins, For example, Pelican t (paditaxel) and Xiang Xie T (d. café d); # (4) constituting enzyme inhibitors, such as Ilinto Tiken (H-age ean) and Topotecan (4); cytotoxic antibiotics, Such as doxorubicin, doxorubicin, mit Xantr〇ne, actinomycin-D and mitomycin, and others, such as etoposide and cui Tretin〇in. The poor, or its municipality, may be hydrolyzed, or may be accompanied by - or a plurality of the above agents, in which case the compound of formula 1 may be administered by systemic or non-systemic means such as topical administration. Hunting is administered by non-monetary means. For example, the other sputum of the present invention is painful. ^ ^, in the temple, provides a treatment for the treatment of drug I or a variety of malignant symptoms to prevent the shadow 妯β 4 + Le things like humans, : Mao! A method of eliminating, which comprises hydrolyzing vinegar in the compound of the present invention, or in a pharmaceutically acceptable form thereof, in another embodiment of the present invention. "A method for preventing hair loss in a warming agent, such as a human, during the period of sexual symptoms, comprising administering to the animal an effective amount of a compound of formula 1, or a pharmaceutically acceptable compound thereof The salt or the in vivo hydrolyzed vinegar, and an effective amount of the agent is administered simultaneously, sequentially or separately. According to another aspect of the invention, a pharmaceutical composition for preventing sub-descendance due to the use of a medicament (4). The hair which is to be caused by the symptoms is dropped, and the compound of the formula 1, or a pharmaceutically acceptable salt thereof, or the in vivo hydrolyzable is used: and the agent is accompanied by a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, the glutinous surface provides a kit comprising a compound of formula (I), or a pharmaceutically acceptable solitude thereof, a hydrolyzable substance in the tongue, and a therapeutic effect for treating malignant symptoms An agent that causes hair to fall is known. According to another aspect of the invention, the support is, for example, a kit comprising: a) a compound of formula (I), or a salt thereof, or a salt or an in vivo hydrolysable ester, The first unit dosage form; b) an agent for treating malignant symptoms, known to be combined with skin loss, causing hair to fall; in a second unit dosage form; and c) for shoulders, the first and the first Container devices in two dosage forms. According to another feature of the invention, there is provided the use of a compound of formula 1, or a pharmaceutically acceptable salt thereof, or a sulphate in vivo, for the manufacture of a medicament for the manufacture of a medicament for the treatment of a ***e Used to prevent hair from falling during heart symptoms. "Further aspect according to the invention" provides a 'mouth' oral treatment for preventing hair from falling, which comprises administering to a warm-blooded animal, such as a human, an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof or Hydrolyzed vinegar in vivo, optionally accompanied by a pharmaceutically acceptable a + μ γ , j diluent or carrier, and at the same time, phase or individual administration of an effective amount of private use for the treatment of malignant symptoms 120858-63- 200811169 As described above, the size of the drug used to treat or prevent the treatment of a particular cell proliferative disorder must vary depending on the host to be treated, the route of administration, and the severity of the condition being treated. A unit dose, for example, in the range of just mg/kg, preferably in mg/kg, is conceivable. The CDK inhibitory activity defined above may be administered mono-therapies or may be involved in addition to the compounds of the invention. One or more other substances and/or treatments. Such co-therapy can be achieved by administering the individual components of the treatment in the same day, in succession or individually. In the field of medical oncology, it is often practiced. Use a combination of different treatment modalities to treat each patient with cancer. In medical oncology, 'the other components of this co-therapy, & the above-mentioned cell cycle inhibition therapy' can be: surgery, ray Therapy or chemotherapy. This chemotherapy can cover two main classes of therapeutic agents: 1 other cell cycle inhibitors, acting by the same or different mechanisms as defined above; (9) cytostatics, such as antiestrogens ( For example, he tam〇xifen, t〇remifene, ral〇xifene, dr〇l〇xifene, iod〇xyfene ), progestogens (such as megestrol acetate), aromatase inhibitors (such as anastrozole, letrazole, vorazde, Yorkmeus) Alkanes (find anti-cutting, anti-progestogens, anti-androgen substances (such as flutamide, mlutamide, bicalutamide, cyproterone) With cesium acetate), LHRH agonists and antagonists (example An inhibitor of g〇sereHn acetate, Luprolide, an anthrone 5 α-dihydroreductase (eg, finasteride), an anti-invasive agent (eg Metalloproteinase inhibitors, examples 120858-64 - 200811169 such as Marimastat, an inhibitor of urokinase plasminogen activator receptor function) and inhibitor of growth factor function (such growth Factors include, for example, platelet-derived growth factors and hepatocyte growth factors, such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors, and serine/threonine kinase inhibitors; Iii) anti-proliferative/anti-tumor drugs and combinations thereof for use in medical oncology, such as antimetabolites (eg, antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purines and glands: y: analogues, arabinose oaths; anti-tumor antibiotics (eg anthracyclines such as polycloseromycin, daunorubicin, epirubicin and idadamycin, mitomycin _c Dakectin, genus a platinum derivative (eg, cisplatin, chloramphenicol) alkylating agent (eg, nitrogen mustard, amphetamine, chlorambucil, chulphan, busulphan, ring) Phosphonamide, ifsfamide, nitrosourea Y thiotepa; anti-mitotic agents (eg, periwinkle plants, such as vincristine, and yew-like materials, such as red beans) Safranol, yew 〇tere); topoisomerase inhibitors (eg epipodophyllotoxin, such as etoposide and diazepam, amsacrine, Topo ^ Ken (t〇P〇teCan)). According to this aspect of the invention, there is provided a pharmaceutical product comprising a compound of formula (1) as defined herein and another anti-tumor shell as defined above for co-therapy of cancer.

之孤’除了其在治療醫藥 /舌體内試驗系統之發展與 用於評估細胞循環活性抑制 如貓、狗、兔子、猴子、大 120858 -65- 200811169 白鼠及老鼠，作為搜尋新穎治療劑之一部份。 在上文其他醫藥組合物、製程、方法、用途及藥劑製造 特徵中’本文中所述本發明化合物之替代與較佳具體實施 例亦適用。 【實施方式】 實例 現在藉由下述非限制性實例說明本發明，其中除非另有 述及，否則·· (1)溫度係以攝氏度數（°C )表示；操作係於環境温度下進 行，意即在18-25t範圍之溫度下； ⑼有機溶液係以無水硫酸鎂脫水乾燥；溶劑蒸發係使用迴 轉式蒸發器，在減壓（600_4000巴斯卡；4.5-30毫米Hg)下，使 用至高60°C之浴溫進行； (Hi)層析係意謂在矽膠上急驟式層析；薄層層析法（丁 LC)係 於矽膠板上進行； (iv)—般而言，反應過程係藉TLC追蹤，且給予反應時間僅 為說明； ⑺最後產物具有令人滿意之質子核磁共振⑼mR)光譜及/ 或質譜數據； (VI)所予之產率僅為說明，而未必是可藉由費心製程發展所 獲得者；若需要較多物質，則重複製備； (vii)當給予NMR數據時，其係呈主要診斷質子之占值形式， 以相對於作為内標準之四甲基矽烷（TMS)之每百萬份之份 數（ppm)表示’於300 MHz下，使用全氣化二甲亞職（DMSOd6) 120858 -66- 200811169 作為溶劑測定，除非另有指出； (viii) 化學符號具有其常用意義；使用SI單位與符號； (ix) 溶劑比例係以體積：體積（v/v)為觀點表示；及 ⑻質譜係在化學電離（CI)模式中，使用直接曝露探測物， 以70電子伏特之電子能操作；其中所指示之離子化作用係 藉由電子碰撞（EI)、快速原子撞擊（FAB)或電喷霧（ESP)達 成；給予m/z之數值；通常僅報告顯示母體質量之離子； (xi) 除非另有述及，否則含有不對稱取代之碳及/或硫原子 之化合物尚未被解析； (xii) 在將一合成描述為類似先前實例中所述者之情況中，所 使用之量係為相當於先前實例中所使用者之毫莫耳比例； (xvi)已使用下列縮寫： BOC 第三-丁氧羰基； IPA 異丙醇； THF 四氫呋喃； DIPEA N，N-二異丙基乙胺； DMAP 4-二甲胺基吡啶； DMF N，N-二甲基甲醯胺； DMF-DMA Ν,Ν-二甲基甲醯胺二甲基縮醛 DMA 二甲基乙醯胺； EtOAc 醋酸乙酯； MeOH 甲醇； ether ***； EtOH 乙醇； 120858 -67- 200811169 HATU 六氣填酸0-(7-氮苯并二ϋ坐-1-基）-1，1-3,3 四甲基4尿， DCM 二氣甲烷； TEA 三乙胺； DMSO 二甲亞颯； TFA 三氟醋酸；及 RPHPLC 逆相南性能液相層析法， (xvii) 用於過濾之PTFE濾器係由Gelman®製造，且包含0.45 //Μ 膜濾器杯。此等可得自Fisher_Scientific UK (零件代碼09730155); (xviii) 在指稱SCX-2或SCX-3管柱之情況下，此係意謂π離子交 換”萃取藥筒，用於鹼性化合物之吸附，意即一種含有苯磺 酸為基料之強陽離子交換吸著劑之聚丙烯管件，根據得自 國際吸著劑技術有限公司（Dyffryn Business Park，Hengeod，Mid Glamorgan，UK，CF82 7RJ)之製造商說明書使用；及 (xix) 用於3-氮雙環并[3.1.0]己烷各胺系統之命名法係示於下 文，其中（Ια，5α，6α)係指在1，5及6位置處之取代基，全部 均在分子之相同面上·In addition to its development in the therapeutic medicine/tongue test system, it is used to evaluate the inhibition of cell cycle activity such as cats, dogs, rabbits, monkeys, large 120858-65-200811169 white mice and mice, as one of the novel therapeutic agents for search. Part. In the above other pharmaceutical compositions, processes, methods, uses and pharmaceutical manufacturing characteristics, the substitutions and preferred embodiments of the compounds of the invention described herein also apply. EXAMPLES The present invention will now be illustrated by the following non-limiting examples, wherein unless otherwise stated, (1) the temperature is expressed in degrees Celsius (° C.); the operation is carried out at ambient temperature, That is, at a temperature in the range of 18-25t; (9) the organic solution is dehydrated and dried with anhydrous magnesium sulfate; the solvent is evaporated using a rotary evaporator, and used under reduced pressure (600_4000 Baska; 4.5-30 mm Hg). (Hi) chromatography means rapid chromatography on silica gel; thin layer chromatography (butyl LC) is carried out on silica gel; (iv) in general, the reaction process Tracing by TLC, and the reaction time is only for explanation; (7) The final product has satisfactory proton nuclear magnetic resonance (9) mR) spectrum and / or mass spectrometry data; (VI) the yield is only illustrative, but not necessarily Obtained by the development of the laborious process; if more substances are needed, repeat the preparation; (vii) When the NMR data is given, it is in the form of the main diagnostic proton, relative to the tetramethyl decane as the internal standard ( TMS) is expressed in parts per million (ppm) At 300 MHz, full gasification of dimethyl sub-s (DMSOd6) 120858-66-200811169 is used as a solvent unless otherwise indicated; (viii) chemical symbols have their usual meaning; use SI units and symbols; (ix) solvents The ratio is expressed in terms of volume: volume (v/v); and (8) mass spectrometry is used in chemical ionization (CI) mode, using direct exposure of the probe, operating at 70 electron volts; the indicated ionization By electron impact (EI), fast atomic impact (FAB) or electrospray (ESP); giving m/z values; usually only ions showing maternal mass are reported; (xi) unless otherwise stated Compounds containing asymmetrically substituted carbon and/or sulfur atoms have not been resolved; (xii) In the case where a synthesis is described as being similar to that described in the previous examples, the amount used is equivalent to that used in the previous examples. (mvi) The following abbreviations have been used: BOC tri-butoxycarbonyl; IPA isopropanol; THF tetrahydrofuran; DIPEA N,N-diisopropylethylamine; DMAP 4-dimethylamino Pyridine; DMF N, N-dimethyl Hydrazine; DMF-DMA Ν, Ν-dimethylformamide dimethyl acetal DMA dimethyl acetamide; EtOAc ethyl acetate; MeOH methanol; ether diethyl ether; EtOH ethanol; 120858-67-200811169 HATU Gas-filled acid 0-(7-azinobenzoindole-1-yl)-1,1-3,3 tetramethyl 4 urine, DCM di-methane; TEA triethylamine; DMSO dimethyl hydrazine; TFA Trifluoroacetic acid; and RPHPLC reverse phase performance liquid chromatography, (xvii) The PTFE filter used for filtration is manufactured by Gelman® and contains a 0.45 // 膜 membrane filter cup. These are available from Fisher_Scientific UK (part number 09730155); (xviii) in the case of the SCX-2 or SCX-3 column, which means a π ion exchange extraction cartridge for the adsorption of basic compounds. , which means a polypropylene pipe fitting containing a strong cation exchange sorbent based on benzenesulfonic acid, manufactured according to Dyffryn Business Park (Hengeod, Mid Glamorgan, UK, CF82 7RJ). The specification is used; and (xix) the nomenclature for the 3-nitrobicyclo[3.1.0]hexane amine system is shown below, where (Ια, 5α, 6α) refers to the 1, 5 and 6 positions. The substituents at the place are all on the same side of the molecule.

Η (此處顯示為全部向下）。 實例1 4-[[4-(2-甲基-3_丙-2-基-咪唑-4_基）嘧啶-2-基]胺基]六氫吡啶-1- 羧酸苄酯 將2-甲氧基乙醇（120毫升）中之（Ε)-3-二甲胺基-1-(2-曱基-3- 120858 -68- 200811169 丙-2-基-咪唑 _4_基）丙 4烯酮（方法 24，WO 03/076436，18.9 克85.46宅莫耳）與4-胺基碳亞胺酿胺基六氫喻咬_ι_叛酸爷 酯（方法1 ; 30.7克，in毫莫耳），於回流下加熱24小時。使 反應混合物冷卻至環境溫度過夜。過濾所形成之沉澱物， 以少量MeOH，接著以醚洗滌，及在真空下乾燥，獲得所需 要之產物，為白色固體（29.8克，80%)。NMR (400.132 MHz， CDC13) L39 (m，2H)，1.48 (d，6H)，2.00 (m，2H)，2·50 (S，3H)，2.94 (m， 2H)，3.92 (m，1H)，4.08 (m，2H)，4.88 (m，1H)，5.07 (s，2H)，5.50 (m，1H)， 6.67 (d，1H)，7.27 (m，6H)，8.13 (d，1H) ; MH+ 435· 實例2 4-(2-甲基_3-丙-2-基-咪唑-4·基）_N_(4-六氮吡啶基）嘧啶-2-胺 將EtOH (500毫升）中之4-[[4_(2_甲基_3·丙-2-基-味唑斗基 &gt;密 咬-2-基]胺基]六氫吡啶_丨_羧酸苄酯（實例i，29·8克，68·5毫 莫耳）與10°/〇 Pd/C (3克）’在40。〇及5巴壓力之氫下擾拌18小 時。濾出觸媒，並蒸發溶劑，獲得透明膠質。以醚研製， 獲得白色固體，將其過濾，並乾燥（19·2克，93%)。NMR (400.132 MHz，CDC13) 1.34 (m，2Η)，1.44 (s，1Η)，1.49 (d，6Η)，1.99 (m，2Η)，2.50 (s，3H)，2·65 (m，2H)，3.06 (m，2H)，3.84 (m，1H)，4·91 (m，1H)，5.57 (m， 1H)，6.65 (d，1H)，7·24 (s，1H)，8.12 (d，1H) ; MH+ 301. 實例3 N-[l-(3-氣基丙基磺醯基）-4_六氫吡啶基卜4_(2-甲基各丙_2_基_ 咪唑-4_基）嘧啶-2_胺 將氯化3-氯丙烷磺醯（1.5毫升，ΐ2·6毫莫耳）慢慢添加至 4-(2-甲基-3-丙-2-基-咪嗤-4-基）Κ4-六氫被。定基）嘴咬-2·胺（實 120858 -69- 200811169 例2; 1.9克，6.3毫莫耳）與ΤΕΑ(2·6毫升，12·6毫莫耳）在；〇(：^ (80毫升）中之懸浮液内。將反應混合物加熱至4〇。〇，歷經卯 分鐘，然後添加另外之氯化；^氯丙烷磺醯（〇·75毫升，6 3毫 莫耳），並將反應物再攪拌2小時。將反應溶液以DCM (7〇 耄升）稀釋，並以水（15〇毫升）洗滌。aDCM(4xl〇〇毫升）萃 取水層。將合併之有機萃液以飽和NaHC〇3水溶液、鹽水洗 滌’脫水乾燥，過濾，及蒸發。使所形成之物質於矽膠上 純化，以5% MeOH/DCM溶離，而得標題化合物，為褐色固 體（770 毫克，28%)。MH+ 441. 實例4 N-(l-爷基-4-六氫吡啶基）_4_(2-甲基各丙_2_基_咪唑_4_基）嘧啶 -2_胺 將濃鹽酸（50毫升）中之4·[[4-(2-甲基-3-丙-2-基-味唑-4_基）嘧 咬-2-基]胺基]六氫吡啶+羧酸苄酯（實例1，7·4克，17毫莫 耳），在100°C下加熱1小時。使反應物冷卻至環境溫度，並 以40% NaOH水溶液中和至ρΗ η。以DCM (4 X 150毫升）萃取 水溶液’並將合併之有機萃液以鹽水洗滌，脫水乾燥，及 蒸發。所形成之物質於矽膠上純化，以10% MeOH/DCM，接 著以MeOH中之20% 2M氨/DCM溶離，獲得兩種產物，經確 認為4-(2-甲基-3-丙-2-基-喷唑冰基）-N-(4-六氫吡啶基）嘴啶-2-胺（實例2，2·3克）與標題化合物（2.4克，36%)。NMR (400.132 MHz) 1.48 (d，6Η)，1.56 (m，2Η)，1.85 (m，2Η)，2.00 (m，2Η)，2.47 (s，3Η)， 2.83 (m，2H)，3.47 (s，2H)，3.70 (m，1H)，5·67 (m5 1H)，6.78 (d，1H)，7.05 (s，1H)，7·25 (m，1H)，7.32 (m，5H)，8.18 (d，1H) ; MH+ 391· 120858 -70- 200811169 實例5 M2-甲基-3-丙-2-基_味唑_4_基外㈣，氫吡咯小基丙基磺醯 基六氫〃比咬基】，咬-2·胺 於已溶解在THF (4毫升）中之Ν—κπ氣基丙基磺醯基六 氫峨咬基]-4-(2-曱基-3-丙-2-基-味。坐-4-基）喷。定-2-胺（實例3，70 毫克，0·16毫莫耳）溶液内，添加碘化鈉（5毫克，〇 〇3毫莫 耳），接著為四氫峨洛（〇·〇5毫升，0.64毫莫耳）。在i5〇°C下， 將反應物藉由微波照射加熱2小時。蒸發溶劑，並使所形成 之物質藉由鹼修正之RPHPLC純化。使所形成之物質溶於 MeOH中’並添加至被Me〇H預潤濕之scx_3管柱中。將管柱 以MeOH沖洗，且產物係以2M氨/MeOH溶離。蒸發溶劑，產 生標題化合物’為黃色固體（47毫克，62〇/〇)。NMR (4〇〇132 MHz， CDC13) 1·54 (m，8H)，1.72 (m，4H)，1.94 (m，2H)，2.08 (m，2H)，2.43 (m， 4H)，2·49 (m，5H)，2.94 (m5 4H)，3.71 (m，2H)，3.89 (m，1H)，4.89 (m，1H)， 5.47 (m，1H)，6.69 (d，1H)，7.24 (s，1H)，8.14 (d，1H) ; MH+ 476. 實例6-8 下列化合物係藉由實例5之程序，並於相同規模下使用 適當胺起始物質製成。 實例 化合物 NMR (400.132 MHz，CDC13) m/z 6 N-[H3-…甲基六氫 吡畊-1-基）丙基續醯 基六氫峨咬基]-4-(2-甲基_3_丙冬基-味 嗤-4-基）嘧咬_2_胺 1·49 (d，6H)，1·57 (m，2H)，1.91 (m5 2H)3 2.08 (m? 2H)? 2.22 (s, 3H)，2.38 (m，10H)，2.50 (s，3H)， 2.93 (m，4H)，3.70 (m，2H)，3.90 (m，1H)，4.88 (m，1H), 5.46 (m， 1H)，6.69 (d5 1H)，7.24 (s，1H), 8.14 (d5 1H) 505 120858 -71 - 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 7 4-(2-甲基-3-丙-2-基-咪唑-4-基）-N-[l-(3-嗎 福啉-4_基丙基磺醯 基M-六氫p比唆基] 嘧啶-2-胺 1·49 (d，6H)，1.57 (m，2H)，1.92 (m，2H)，2.09 (m，2H)，2.38 (m， 6H)，2.50 (s，3H)，2.93 (m，4H)， 3.63 (m，4H)，3.70 (m，2H)，3.91 (m，1H)，4.89 (m，1H)，5.46 (m， 1H)，6.69 (d，1H)，7.24 (s，1H)， 8.14 (d，1H) 492 8 2-[4-[3-[[4-[[4_(2-甲基 -3-丙-2-基米。坐-4-基） 嘧啶-2-基]胺基]-1-六 氫吡啶基]磺醯基] 丙基]六氫吡畊-1-基]乙醇 1.48 (d，6H)，1·56 (m，2H)，1.91 (m，2H)，2.08 (m，2H)，2.43 (m， 15H)，2.61 (s，1H)，2.93 (m，4H)， 3.54 (m，2H)，3·70 (m，2H)，3.90 (m，1H)，4.89 (m，1H)，5·46 (m， 1H)，6.69 (d，1H)，7.24 (s，1H)， 8.14 (d，1H) 535 實例9 2-[3-[[4_[[4_(2-甲基-3-丙-2-基_哺嗤-4-基）喊咬-2_基】胺基]-1-六氫 吡啶基]磺醯基】丙胺基]丁 -1-醇 於已溶解在THF (4毫升）中之N-[l-(3-氯基丙基磺醯基）-4-六 氫竹(：咬基]-4-(2-甲基-3-丙-2-基-味唾冰基）嘴唆-2-胺（實例3，70 毫克’ 0.16毫莫耳）溶液内，添加碘化鈉（5毫克，〇 03毫莫 耳）’接著為2-胺基·1·丁醇（〇·22毫升，2.38毫莫耳）。在150°C 下’將反應物糟由微波照射加熱2小時。蒸發溶劑，並使所 形成之物質藉由鹼修正之RPHPLC純化。使所形成之物質溶 於MeOH中，並添加至被MeOH預潤濕之SCX-3管柱中。將管 柱以MeOH沖洗，且產物係以2M氨/MeOH溶離。蒸發溶劑， 產生^通化合物’為白色固體（36毫克，46%)。NMR (400.132 MHz，CDC13) 0.85 (t，3H)，1.30-1.49 (m，8H)，1.57 (m5 2H)，1.91 (m5 2H)， 2.08 (m，2H)，2.47 (m，4H)，2·63 (m，1H)，2.80 (m，1H)，2.95 (m5 4H)，3.24 (m，1H)，3.56 (m，1H)，3.70 (m，2H)，3.91 (m，1H)，4.92 (m，1H)，5.46 (m， 120858 -72- 200811169 1H)，6.69 (d，1H)，7.24 (s，1Η)，8· 14 (d，1H) ; MH+ 494. 實例10-14 下列化合物係藉由實例9之程序，並於相同規模下使用 適當胺起始物質製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 10 N-[l-[3-(l-甲氧基丙 -2-基胺基）丙基續 醯基]-4-六氫p比咬 基]-4-(2-甲基-3·丙 -2-基-咪嗤-4·基）口密 啶-2-胺 0.94 (d，3H)，1.49 (d，6H)，1.56 (m，2Η)，1·90 (m，2Η)，2·08 (m， 2H)，2·50 (s，3H)，2_68 (m，2H)， 2.80 (m，1H)，2·97 (m，4H)，3.14 (m，1H)，3.25 (m，1H)，3.28 (s， 3H)，3J1 (m，2H)，3.90 (m，1H)， 4.89 (m，1H)，5·47 (m，1H)，6.69 (d，1H)，7.24 (s，1H)，8·14 (d，1H) 494 11 丙·2-基·咪峻-4-基） 嘧啶-2-基]胺基]-1_ 六氫吡啶基]續醯 基]丙胺基]丙-2-醇 1.09 (d，3H)，1.49 (d，6H)，1.57 (m，2H)，L92 (m，2H)，2.09 (m， 2H)，2.36 (m，1H)，2.50 (s，3H)， 2.70 (m，3H)，2.95 (m，4H)，3.71 (m，3H)，3.91 (m，1H)，4.92 (m， 1H)，5.46 (m，1H)，6·69 (d，1H)， 7.24 (s，1H)，8.14 (d，1H) 480 12 2-[3-[[4-[[4-(2甲基-3-丙-2-基-咪嗤-4-基） 嘧啶-2-基]胺基]-1-六鼠峨σ定基]續酿 基]丙胺基]丙-1 -酉孚 (399.902 MHz) 0.99 (d，3H)，1_48 (d，6H)，1.57 (m，2H)，1.92 (m， 2H)5 2.08 (m5 2H)5 2.50 (s5 3H)5 2.61 (m，1H)，2.71 (m, 1H)，2.82 (m，1H)，2.96 (m，4H)，3.19 (m， 1H)，3.52 (m，1H)，3·70 (m，2H)， 3.91 (m，1H)，4.93 (m，1H)，5.46 (m，1H)，6.69 (d，1H)，7.24 (s， 1H)，8.14 (d，1H) 480 13 3-曱基-2-[3-[[4-[[4-(2-甲基-3-丙-2-基米 唑-4-基）嘧啶-2-基] 胺基]-1-六氫说σ定 基]磺醯基]丙胺基] 丁 -1-醇 0.83 (d，3H)，0.90 (d，3H)，1.49 (d， 6H)，1.57 (m，2H)，1.73 (m，1H)， 1.91 (m，2H)，2.08 (m，2H)，2.31 (m，1H)，2.50 (s，3H)，2.63 (m， 1H)，2.80 (m，1H)，2.95 (m，4H)， 3.27 (m，1H)，3·55 (m，1H)，3.71 (m，2H)，3.91 (m，1H)，4.91 (m， 1H)，5.46 (m，1H)，6.69 (d，1H)， 7.24 (s，1H)，8.14 (d，1H) 508 120858 -73 · 200811169 實例 化合物 NMR (400.132 MHz, CDC!3) m/z 14 2-曱基-2-[3-[[4-[[4-(2-甲基-3-丙-2-基-咪 唑-4_基）嘧啶-2-基] 胺基]-1-六氣批°定 基]績醯基]丙胺基] 丙-1-酉芋 1.00 (s，6H)，1.49 (d，6H)，1.57 (m，2H)，1.88 (m，2H)，2.08 (m， 2H)，2.50 (s，3H)，2.60 (m，2H)， 2.96 (m，4H)，3.23 (s，2H)，3.70 (m，2H)，3.91 (m，1H)，4·92 (m， 1H)，5.46 (m，1H)，6·69 (d，1H)， 7.24 (s，1H)，8.14 (d，1H) 494 實例15 Ν·[1-[3·(2-甲氧基乙胺基）丙基續醯基】-4-六氫p比唆基】-4-(2-甲 基-3_丙-2-基-味嗤_4_基）喊唆-2_胺 於已溶解在THF (3毫升）中之N-[l-(3-氯基丙基磺醯基）-4-六 氫p比11 定基]-4-(2·曱基-3-丙-2-基-味ti坐-4·基）嘴淀-2-胺（實例3，42 毫克，0.09毫莫耳）溶液内，添加碘化鈉（3毫克，〇.〇2毫莫 耳），接著為2-甲氧基乙胺（〇·14毫升，1.4毫莫耳）。在150°C 下’將反應物藉由微波照射加熱2小時。過遽反應混合物， 並蒸發濾液。使所形成之物質溶於DCM中，並於矽膠上純 化，以MeOH中之5% 2M氨/DCM溶離。合併含有產物之溶離 份，及蒸發，而得膠質，將其以醚研製，獲得標題化合物， 為黃色固體（36 毫克，79%)。NMR (400.132 MHz，CDC13) 1.49 (d， 6H)，1.60 (m，2H)，2·11 (m，4H)，2.51 (s，3H)，2·94 (m，6H)，3.09 (m，2H)， 3.32 (s，3H)，3.57 (m，2H)，3.72 (m，2H)，3.91 (m，1H)，4.99 (m，1H)，5.47 (m，1H)，6.69 (d，1H)，7.26 (s，1H)，8.14 (d，1H) ; MH+ 480. 實例16 3_[[4_[[4_(2_曱基-3-丙_2·基-咪唑冰基）嘴啶：基]胺基]小六氫吡 啶基]磺醯基]丙-1-醇 使N-[l-(3-氯基丙基磺醯基）冰六氫吡啶基]_4-(2_甲基-3-丙-2- 120858 -74 - 200811169 米坐4-基）π笛啶·2·胺（實例3,5〇毫克，〇 ιι毫莫耳）溶於段 (4笔升）中，添加醋酸鈉（47毫克，0.57毫莫耳）與碘化鈉（5 笔克，0.03毫莫耳），並在14〇t下，將反應物藉由微波照射 加熱1小時。過濾反應混合物，並以EtOH洗滌。將2M NaOH (3笔升）添加至濾液中，並將溶液於環境溫度下攪拌1小時。 以2M HC1水溶液使反應溶液中和至阳7，且蒸發溶劑。使 所形成之物質KDCM與水之間作分液處理。使有機相之内 含物於矽膠上純化，在5_1〇% MeOH/DCM之梯度液上溶離。 將έ有產物之溶離份合併’並蒸發成膠質，將其以鱗研製， 而得標題化合物，為黃色固體（17毫克，36%)。nmR (399 9〇2 MHz，CDC13) 1.55 (m，8H)，1.7G (m，lH)，2.G5 (m，4H)，2.5G (s，3H)，2.93 (m，2H)，3.02 (m，2H)，3.73 (m，4H)，3.90 (m，1H)，4·91 (m，1H)，5.46 (m， 1H)，6.69 (d，1H)，7·24 (s，1H)，8.14 (d，1H)，MH+ 423· 實例17 4_[[4_(2-曱基-3_丙·2_基咪唑-4-基）鳴啶_2_基]胺基】六氫吡啶小 磺醯胺 將二氧陸圜中之4-(2-甲基-3-丙-2-基_味唑斗基）_N-(4-六氫吡 啶基）嘧唆-2-胺（實例2，60毫克，0.2毫莫耳）與確醯胺（192 耄克’ 2宅莫耳）’於回流下加熱16小時。使反應物冷卻至 環境溫度，並以水（50毫升）與飽和NaHC03水溶液（50毫升） 稀釋。以DCM (5 X 50毫升）萃取水溶液。蒸發合併之有機物 質，且使所形成之物質溶於具有少量MeOH之DCM中，及於 矽膠上純化，以0-10% MeOH/DCM之梯度液溶離。合併含有 產物之溶離份，並蒸發，而得標題化合物，為白色固體（4〇 120858 -75- 200811169 毫克 ’ 53%)。NMR (400.132 MHz，CDC13) 1.49 (d，6H)，1.61 (m，2H)， 2.10 (m，2H)，2·50 (s，3H)，2_84 (m，2H)，3·64 (m5 2H)，3.88 (m，1H)，4.39 (s，2H)，4.96 (m，1H)，5.48 (m，1H)，6.69 (d，1H)，7.25 (s，1H)，8.14 (d， 1H) ； MH+ 380. 實例18 N，N-二甲基-4-[【4-(2_甲基_3_丙-2_基咪唑_4_基）峨啶_2_基】胺基] 六氫吡啶-1_績醯胺 將DCM (1毫升）中之氯化二甲基胺磺醯（〇 〇26毫升，〇·24毫 莫耳）逐滴添加至4-(2-甲基-3-丙-2·基^米唑斗基）-Ν-(4-六氫吡 咬基）嘴ϋ定-2-胺（實例2 ; 60毫克，〇·2毫莫耳）與TEA (0.084毫 升’ 0·6毫莫耳）在DCM (1毫升）中之經攪拌溶液内。將溶液 於環境溫度下攪拌16小時。添加水(2毫升），然後，使混合 物經過PTFE杯過濾’並於矽膠上純化，以…5% Me〇H/DCM 之梯度液溶離’獲得固體。以驗研製，接著再蒸發，獲得 寺不通化合物’為無色固體（62 ^:克，76%)。NMR (400.132 MHz， CDC13) 1.49 (d，6H)，1.55 (m，2H)，2.06 (m，2H)，2·50 (S，3H)，2.76 (S， 6H)，2·92 (m，2H)，3·62 (m，2H)，3.88 (m，1H)，4·88 (m，1H)，5·49 (m，1H)， 6.69 (d，1H)，7.25 (s，1H)，8.14 (d，1H) ; MH+ 408. 實例19 4_[[4-(2-甲基-3-丙-2-基-味唑_4-基）嘧啶丨基】胺基】六氫吡啶小 綾醯胺 使4-(2-甲基-3_丙_2_基·味唑斗基&gt;N_(4_六氫吡啶基鴻啶冬 胺（實例2; 150毫克，0.5毫莫耳）溶於THF(5毫升）中，並添 加氰酸鉀（163毫克，2.0毫莫耳）在水（1毫升）中之溶液。使 120858 -76- 200811169 所形成之溶液冷卻至〇它，並添加1M HC1 (2毫升）。將反應 混合物在(TC下攪拌2小時，然後溫熱至環境溫度過夜。將 反應混合物施加至5克SCX-3管柱，以水（2xl0毫升）、Me〇H (2 X 10毫升）洗滌，接著以3·5Ν丽3颜6〇11 (2 X 1〇毫升）溶離。 於真玉中移除溶劑，獲得無色膠質，將其以醚研製，過濾， 亚乾燥，而得標題化合物，為無色固體（142毫克，83%)。 NMR (400 MHz, CDC13) 1.44-1.59 (m5 8H)5 2.10 (d5 2H)5 2.57 (s5 3H), 3.02 (t5 2H)3 3.88^4.07 (m? 3H), 4.42 (brs, 2H)? 4.90-5.03 (m5 1H), 5.49-5.64 (m，1H)，6.75 (d，1H)，7.31 (s，1H)，8.21 (d，1H) ; MH+ 344_ 實例20 N，N-二甲基_4_[[4-(2-甲基-3-丙_2_基_喃唑冬基）鳴啶-2·基】胺基] 六氮p比咬-1·叛釀胺 使4-(2•甲基-3-丙_2_基-咪唑斗基）_Ν_(4·六氫吡啶基）嘧啶_2_ 胺（實例2 ; 150毫克，〇.5〇毫莫耳）與ΤΕΑ (〇丨毫升，〇 75毫莫 耳）溶於DCM (5毫升）中。添加二甲基氯化胺甲醯（〇.〇6毫升）， 並將反應物在惰性大氣下攪拌16小時。添加緩血酸胺樹脂 (150毫克），將反應混合物攪拌1小時，然後經過矽藻土填 充柱過濾，及在真空中蒸發。以醚研製，獲得標題化合物， 為無色固體（81 毫克，44%)。NMR (4〇〇 MHz) 1.39-1.57 (m，8H)，L87 (d，2H)，2.48 (s，3H)，2.69-2.84 (m，8H)，3.57 (d，2H)，3·79-3·93 (brs，1H)， 5.74-6.54 (brs，1H)，6.80 (d，1H)，6.97-7.23 (brs，1H)，7.34 (s，1H)，8.12 (d， 1H) ； MH+ 372. 實例21 N-甲基-4-[[4-(2-甲基-3-丙-2_基-味唑冬基）峨啶：基】胺基】六氫 120858 -77- 200811169 吡啶-1-羧醯胺 標題化合物係藉由實例109之程序，並於相同規模下使用 4-(2•甲基-3-丙-2-基-味唑-4-基）-Ν·(4-六氫吡啶基）嘴啶-2-胺（實 例 2)作為起始物質而製成。NMR (CDC13) 2.19 (m，7Η)，2.27 (q， 1H)，2.49 (t，1H)，2.79 (s，3H)，2.82 (d，3H)，2.97 (dd，2H)，3.86-4.05 (m， 3H)，4·46 (d，1H)，5.04-5.24 (brs，1H)，5.48-5.68 (m，1H)，6.74 (d，1H)，7.32 (s，2H)，8.19 (d，1H). 實例22 (4_甲基-1，4-二氮七圜烷小基）_[4_[[4-(2-甲基-3-丙-2-基-哺唑-4-基），咬-2-基】胺基]-1-六氮p比咬基】甲嗣 於惰性大氣下，將氯曱酸4-硝基苯酯（ill毫克，〇·55毫莫 耳）添加至4-(2-曱基各丙-2-基-味唑-4-基）-Ν-(4-六氫吡啶基）嘧 啶-2-胺（實例2; 151毫克，〇·5毫莫耳）與ΤΕΑ(0.15毫升，1.10 毫莫耳）在二氧陸圜（5毫升）中之經攪拌溶液内。2小時後， 添加Ν-甲基高六氫吡啡（0.069克，0.6毫莫耳），並將反應物 於80°C下加熱4小時。然後，在真空中蒸發混合物，並使殘 留物溶於EtOAc (10毫升）中，且以IN NaOH (5 X 10毫升），接 著以鹽水洗滌。使有機層脫水乾燥，過濾，及蒸發，獲得 固體。將殘留物裝載至SCX-2管柱，以水、MeOH，然後以 3.5N NH3/MeOH洗滌，而得標題化合物，為黃色固體（78毫 克，35%)。NMR (CDC13，400 MHz) 1.44-1.58 (m，8H)，1.87-1.96 (m，2H)， 2.08 (d，2H)，2.36 (s，3H)，2.52-2.60 (m，5H)，2.62-2.70 (m，2H)，2.88 (t， 2H)，3·42-3·52 (m，4H)，3_60 (d，2H)，3.89-4.02 (m，1H)，4·98 (brd，1H)， 5.51-5.67 (表觀寬廣，1H)，6.74 (d，1H)，7.31 (s，1H)，8.20 (d，1H); MH+ 120858 -78- 200811169 441. 實例23-28 下列化合物係藉由實例22之程序，並於相同規模下利用 適當胺 [?¥] ，且藉RPHPLC另外i 化合物 也彳匕而製成。__ NMR (400.132 MHz, CDC13) m/z 23 N-(l-曱基-4-六氫p比 啶基）-4-[[4-(2-甲基-3-丙-2-基·咪。坐-4-基）嘴 啶-2-基]胺基]六氫 吡啶-1-羧醯胺 1.41-1.58 (m，8H)，1.91-2.19 (m，6H)，2·29 (s5 3H)，2.57 (s， 3H)，2·81 (d，2H)，2.96 (t，2H), 3.61-3.74 (m，1H)，3.86-4.05 (m，3H)，4.29 (d，1H)，4.96 (d， 1H)，5.49-5.67 (s，1H)，6.75 (d， 1H)，7.31 (s，1H)，8·20 (d，1H) 441.6 24 N-[[(2S)-1-乙基四氮 吡咯-2-基]甲基]-4-[[4-(2-甲基 _3-丙-2-基· 咪η坐_4_基）π密咬-2-基] 胺基]六氫ρ比17定-1-叛 醯胺 1.09 (t，4H)，1.40-1.78 (m， 12H)，1.79-1.93 (m，1H)，2.07 (d，2H)，2.12-2.30 (m，2H)， 2·57 (s，3H)，2.58-2.68 (m，1H)， 2.72-2.86 (m，1H)，2.97 (t，2H)， 3.17 (brd5 2H)5 3.34-3.46 (m5 1H)，3.79-4.08 (m，3H)，4.97 (d，1H)，5.18-5.43 (brs，1H)， 5.50-5.65 (brs，1H)，6.74 (d， 1H)，7.31 (s，1H)，8.20 (d，1H) 455.6 25 N-[[(2R)_1-乙基四氫 p比洛-2-基]甲基]-4-[[4-(2-甲基-3-丙-2-基_ 咪嗤-4-基）,咬-2-基] 胺基]六氫吡啶-1-羧 醯胺 1.09 (t5 4H)，1.40-1.78 (m， 10H)，1.79-1.93 (m，1H)，2.07 (d，2H)，2.12-2.30 (m，2H)， 2.57 (s，3H)，2.58-2.68 (m，1H)， 2.72-2.86 (m，1H)，2.97 (t，2H)， 3.17 (brd，2H)，3.34-3.46 (m， 1H)，3.79-4.08 (m，3H)，4·97 (appd，1H)，5.18-5.43 (brs，1H)， 5.50-5.65 (brs，1H)，6.74 (d， 1H)，7.31 (s, 1H)，8·20 (d，1H) 455.6 26 N-(2-二曱胺基-乙 基）冰[[4-(2-甲基-3-丙 -2-基-咪唑-4-基）嘧啶 -2-基]胺基]六鼠口比 啶小羧醯胺 415.6 120858 -79- 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 27 [(3S)-3_二曱胺基-四 氮 ϊ7比洛-1-基] (2-甲基-3-丙-2-基-σ米 。坐-4-基）嘴淀-2-基]胺 基&gt;1-六氫外b σ定基] 甲酮 1.39-1.59 (m，8H)，1.69-1.81 (m，1H)，2.00-2.13 (m，3H)， 2.27(s，6H)，2.57(s，3H)，2.59-2.69 (m, 1H), 2.81-3.01 (m， 2H)，3.23 (t，1H)，3.40-3.58 (m， 3H)，3.73 (t，2H)，3.93-4.05 (m， 1H)，4.99 (brd，1H)，5.51-5.67 (brs，1H)，6.74 (d，1H)，7.31 (s， 1H)，8.20 (d，1H) 441.6 28 4-[[4-(2·甲基-3_丙 _2_ 基-味唑-4-基）嘧啶_2_ 基]胺基]_Ν-(2-四氫 外匕17各-1·基乙基）六氫 吡啶小羧醯胺 1.41-1.58 (m，9H)，1.74-1.81 (m，3H)，2.03-2.11 (m，2H)， 2·49-2_55 (m，4H)，2.57 (s5 3H)， 2.62 (t，2H)，2.96 (t，2H)，3.34 (q，2H)，3.87-4.05 (m，3H)， 4.97 (d，1H)，5.17-5.26 (brs， 1H)，5.49-5.64 (m，1H)，6.74 (d，1H)，7.31 (s，1H)，8.21 (d， 1H) 441.6 實例29 l-[4-[[4-(2-甲基·3_丙-2_基-味唑冰基㈣啶冬基】胺基】小六氫吡 啶基]乙酮 使4-(2-甲基-3-丙-2-基“米唑斗基六氫吡啶基㈣啶_2_ 胺（實例2 ’ 83毫克’ 0.28毫莫耳）懸浮於DCM (2毫升）中。添 加TEA (0.077毫升’ 0.55毫升），接著為dCM (1毫升）中之醋酸 酐（0.03毫升，0.30毫莫耳），歷經一分鐘期間。將反應物於環 境溫度下攪拌3天。將反應溶液以飽和NaHC〇3水溶液洗滌， 經過PTFE杯過濾，且蒸發溶劑，而得標題化合物，為白色 泡沫物（72 毫克，77%)。NMR (400.132 MHz，CDC13) 1.39 (m，2H)， 1.49 (d，6H)，2.05 (m，5H)，2.50 (s5 3H)，2·78 (m，1H)，3_14 (m，1H)，3.76 (m，1H)，3·98 (m，1H)，4.45 (m，1H)，4.90 (m，1H)，5.49 (m，1H)，6.69 (d， 1H)，7.25 (s，1H)，8.14 (d，1H) ; MH+ 343· 120858 -80- 200811169 實例30 l-[4-[[4-(2-甲基-3_丙：基咪唑冰基）嘧啶：基】胺基】4六氫吡 啶基】-4-嗎福淋_4_基-丁小酮 將DMF (2毫升）中之4-(2-甲基-3-丙-2-基-味唑-4-基）-N-(4-六 氫1^ &quot;定基）哺啶_2_胺（實例2，60毫克，0.2毫莫耳）、4-嗎福啉 -4-基丁酸鹽酸鹽（方法3 ; 5〇毫克，〇·24毫莫耳）' HATU (91 耄克，0.24毫莫耳）及DIPEA (〇14毫升，〇 8毫莫耳），於環境 溫度下擾拌過夜。蒸發溶劑，並使所形成之物質於DCM (2 毫升）與飽和NaHC〇3水溶液（2毫升）之間作分液處理，經過 PTFE杯重力過濾，並蒸發。使所形成之物質溶於dcm中， 並於矽膠上純化，以〇_1〇% Me〇H/DCM之淺梯度液溶離。合 併含有產物之溶離份，及蒸發，而得標題化合物，為白色 玻璃態固體（64 毫克，70%)。NMR (400.132 MHz，CDC13) 1.39 (m， 2H)，1.49 (d，6H)，1.78 (m，2H)，2·05 (m，2H)，2.39 (m，8H)，2.50 (s，3H)， 2·78 (m，1H)，3.12 (m，1H)，3.65 (m，4H)，3.82 (m，1H)，3.98 (m，1H)，4·45 (m，1H)，4.89 (m，1H)，5.49 (m，1H)，6·69 (d，1H)，7.25 (s，1H)，8.14 (d， 1H) ； MH+ 456. 實例31 N_(l-甲基-4_六氫吡啶基）_4-(2_甲基各丙_2_基-咪唑冬基啶 胺 使4-(2-甲基-3-丙-2-基-味唑-4-基）-N-(4-六氫吡啶基）嘴啶 胺（實例2，50毫克，0.17毫莫耳）溶於THF(2毫升）中。添加 @曰騃（〇_〇1毫升，017毫莫耳），其會造成物質之沉澱作用。 、加甲备水》谷液（37%，1耄升），會造成沉殿物溶解。將反 120858 -81 - 200811169 應物於環境溫度下攪拌30分鐘。添加三乙醯氧基硼氫化鈉 (100毫克），並將反應物再攪拌2小時。蒸發溶劑，並以飽 和NaHC〇3水溶液使所形成之物質中和，且以DCM (15毫升） 萃取，經過PTFE杯過濾，及添加至矽膠管柱中。使管柱以 MeOH中之0-20% 2M氨/DCM之淺梯度液溶離。合併含有產物 之 &gt;谷離份’並蒸發’而得標題化合物，為白色固體（％毫克， 63%)。NMR (400.132 MHz，CDC13) 1.52 (m，8H)，2.01 (m，4H)，2.23 (s， 3H)，2.50 (s，3H)，2·76 (m，2H)，3.75 (m，1H)，4.90 (m，1H)，5·57 (m iH) 6.65 (d，1H)，7·24 (s，1H)，8.12 (d，1H) ; MH+ 315. 實例32 4_(2-甲基-3-丙-2_基_咪唑_4_基）具(1-丙_2-基_4-六氩吡咬基）, 啶-2-胺 使4_〇曱基_3·丙基-味唑_4_基）-N-(4_六氫吡啶基）σ密咬_2胃 胺（實例2，70毫克，0·23毫莫耳）懸浮於丙酮（3毫升）中。添 加醋酸（0.013毫升，0.23毫莫耳），接著為DCM (1毫升），以 幫助溶解。將反應物於環境溫度下攪拌30分鐘。添加三乙 醯氧基硼氫化鈉（99毫克，〇·47毫莫耳），並將反應物留置擾 拌16小時。施行進一步添加三乙醯氧基硼氫化鈉（2〇〇毫克， 0.94毫莫耳），並將反應物在40°C下加熱過夜。蒸發溶劑， 且以飽和NaHC〇3水溶液使殘留物中和，與DCM —起振盡， 及經過PTFE杯過濾、。蒸發DCM溶劑，獲得透明油。添加醚， 並使溶液再蒸發。將所形成之油置於高真空下，而得標題 化合物，為白色固體（45 毫克，56%)。NMR (400.132 MHz，CDC13) 0.98 (d，6H)，1.49 (m，8H)，1.99 (m，2H)，2.21 (m，2H)，2.50 (s，3H)，2·67 120858 -82- 200811169 (m，1H)，2.80 (m，2H)，3.75 (m，1Η)，4·91 (m，1H)，5.57 (m，1H)，6.64 (d， 1H)，7.24 (s，1H)，8.12 (d，1H) ; MH+ 343. 實例33 4_(2_甲基-3-丙-2-基-哺嗅基）-N-(l-苯乙基_4_六氫p比咬基）嘴 咬-2-胺 將DMF (2毫升）中之4-(2-甲基-3-丙-2-基-味唑冰基）-N-(4-六 氫吡啶基）喊啶冬胺（實例2，70毫克，0.23毫莫耳）、2-溴基 乙苯（65毫克，0·35毫莫耳）及TEA(0·097 毫升，0·7毫莫耳）， 在50°C下加熱65小時。使溫度增加至90°C，歷經2小時，然 後蒸發溶劑。使所形成之物質溶於DCM中，並於矽膠上層 析，以0-10% MeOH/DCM之淺梯度液溶離。合併含有產物之 溶離份，且蒸發成膠質，添加醚，再蒸發，及於真空下乾 燥，而得標題化合物，為白色固體（33毫克，35%)。NMR (400.132 MHz，CDC13) 1.59 (m，8H)，2.08 (m，2H)，2·20 (m，2H)，2.57 (s， 3H)，2·62 (m，2H)，2·82 (m，2H)，2.97 (m，2H)，3·86 (m，1H)，4.99 (m，1H)， 5.63 (m，1H)，6·72 (d，1H)，7.21 (m，3H)，7.29 (m，3H)，8·20 (d，1H); MH+ 405· 實例34 4-[[4-(2-甲基-3-丙-2·基-味唑-4-基）嘧啶-2-基]胺基]六氫吡啶·1-羧酸第三-丁酯 將已溶於THF (1毫升）中之碳酸（2-甲基丙-2-基）氧基羰基 第三-丁酯（44毫克，0.2毫莫耳）添加至已溶於thF (3毫升） 中之4-(2-曱基-3-丙-2-基·味唑斗基）-Ν_(4-六氫吡啶基）嘧啶-2-胺（實例2，60毫克，〇·2毫莫耳）溶液内。將反應混合物在 120858 -83 - 200811169Η (shown here as all down). Example 1 4-[[4-(2-Methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino] hexahydropyridine-1-carboxylic acid benzyl ester 2- (Ε)-3-dimethylamino-1-(2-mercapto-3- 120858-68-200811169 propan-2-yl-imidazole-4-yl)propanoid in methoxyethanol (120 ml) Enone (Method 24, WO 03/076436, 18.9 g 85.46 house Moule) with 4-aminocarbimimine-branched amine hexahydro-bite _ι_ oxalic acid ester (method 1; 30.7 g, in millimolar Ear), heated under reflux for 24 hours. The reaction mixture was allowed to cool to ambient temperature overnight. The resulting precipitate was filtered, washed with EtOAc EtOAc EtOAc EtOAc NMR (400.132 MHz, CDC13) L39 (m, 2H), 1.48 (d, 6H), 2.00 (m, 2H), 2·50 (S, 3H), 2.94 (m, 2H), 3.92 (m, 1H) , 4.08 (m, 2H), 4.88 (m, 1H), 5.07 (s, 2H), 5.50 (m, 1H), 6.67 (d, 1H), 7.27 (m, 6H), 8.13 (d, 1H); MH+ 435· Example 2 4-(2-Methyl-3-propan-2-yl-imidazol-4-yl)-N-(4-hexaazinopyridyl)pyrimidin-2-amine 4 of EtOH (500 mL) -[[4_(2_methyl_3·propan-2-yl-isoxazole)&gt; dimethyl-2-yl]amino] hexahydropyridine 丨 丨 carboxylic acid benzyl ester (example i, 29· 8 g, 68·5 mmol) and 10 ° / 〇 Pd / C (3 g) 'distracted for 18 hours under 40 Torr and 5 bar of hydrogen. Filter out the catalyst and evaporate the solvent to obtain transparency The gums were triturated with ether to give a white solid, which was filtered and dried (19·2 g, 93%). NMR (400.132 MHz, CDC13) 1.34 (m, 2 Η), 1.44 (s, 1 Η), 1.49 (d ,6Η), 1.99 (m, 2Η), 2.50 (s, 3H), 2·65 (m, 2H), 3.06 (m, 2H), 3.84 (m, 1H), 4·91 (m, 1H), 5.57 (m, 1H), 6.65 (d, 1H), 7·24 (s, 1H), 8.12 (d, 1H); MH+ 301. Example 3 N-[l-(3-cyclopropylsulfonyl) -4_hexahydropyridyl b 4_(2-methylpropan-2-yl-imidazol-4-yl)pyrimidine-2-amine will be chlorinated 3-chloropropane sulfonium sulfonate (1.5 ml, ΐ2·6 毫Moore) was slowly added to 4-(2-methyl-3-propan-2-yl-amido-4-yl)indole 4-hexahydro- hexyl)-------------------------- 200811169 Example 2; 1.9 g, 6.3 mmoles) and hydrazine (2.6 ml, 12·6 mmol) in a suspension in 〇 (:^ (80 ml). Heat the reaction mixture to 4 〇. 〇, after 卯 minute, then add another chlorination; chloropropane sulfonate (〇·75 ml, 6 3 mmol), and the reaction was stirred for another 2 hours. The reaction solution was DCM (7 〇耄) Dilute and dilute and wash with water (15 ml). The aqueous layer was extracted with aDCM (4×1 mL). The combined organic extracts were washed with saturated aqueous NaHCI3, brine, dried, filtered, and evaporated. The resulting material was purified on EtOAc EtOAc (EtOAc) MH+ 441. Example 4 N-(l-G-yl-4-hexahydropyridyl)_4_(2-methylpropan-2-yl-imidazolyl-4-yl)pyrimidine-2-amine. Concentrated hydrochloric acid (50 ml 4·[[4-(2-methyl-3-propan-2-yl-isoxazole-4-yl)pyridin-2-yl]amino]hexahydropyridine + benzyl carboxylate (example) 1,7·4 g, 17 mmol, heated at 100 ° C for 1 hour. The reaction was cooled to ambient temperature and neutralized to pH η with 40% aqueous NaOH. The aqueous solution was extracted with DCM (4 X 150 mL) and the combined organic extracts were washed with brine, dried and evaporated. The resulting material was purified on silica gel eluting with 10% MeOH / DCM followed by 20% 2M ammonia / DCM in MeOH to afford the product, which was identified as 4-(2-methyl-3-prop-2- -N-Pyrazole-based aryl-N-(4-hexahydropyridinyl)-l-pyridin-2-amine (Example 2, 2.3 g) and the title compound (2.4 g, 36%). NMR (400.132 MHz) 1.48 (d,6Η), 1.56 (m,2Η), 1.85 (m,2Η), 2.00 (m,2Η), 2.47 (s,3Η), 2.83 (m,2H), 3.47 (s , 2H), 3.70 (m, 1H), 5.67 (m5 1H), 6.78 (d, 1H), 7.05 (s, 1H), 7·25 (m, 1H), 7.32 (m, 5H), 8.18 (d,1H) ; MH+ 391· 120858 -70- 200811169 Example 5 M2-methyl-3-propan-2-yl-isoxazole_4_yl (4), hydropyrrolidinylpropylsulfonylhexahydroindole Than the bite base, biting -2. amine in the THF (4 ml) has been dissolved in the Ν - κ π propyl propyl sulfonyl hexahydro carbazyl] -4- (2-mercapto-3- propyl - 2-Base-flavor. Sit-4-yl) spray. In a solution of dimethyl-2-amine (Example 3, 70 mg, 0·16 mmol), add sodium iodide (5 mg, 〇〇3 mmol), followed by tetrahydrofuran (〇·〇5 ml) , 0.64 millimoles). The reaction was heated by microwave irradiation for 2 hours at i5 °C. The solvent was evaporated and the material formed was purified by RPHPLC, which was modified by base. The formed material was dissolved in MeOH' and added to a scx_3 column pre-wetted with Me〇H. The column was rinsed with MeOH and the product was eluted with 2M ammonia / MeOH. The solvent was evaporated to give the title compound <RTI ID=0.0> NMR (4〇〇132 MHz, CDC13) 1·54 (m, 8H), 1.72 (m, 4H), 1.94 (m, 2H), 2.08 (m, 2H), 2.43 (m, 4H), 2·49 (m, 5H), 2.94 (m5 4H), 3.71 (m, 2H), 3.89 (m, 1H), 4.89 (m, 1H), 5.47 (m, 1H), 6.69 (d, 1H), 7.24 (s , 1H), 8.14 (d, 1H); MH+ 476. Examples 6-8 The following compounds were prepared by the procedure of Example 5 and using the appropriate amine starting materials on the same scale. Example compound NMR (400.132 MHz, CDC13) m/z 6 N-[H3-...methylhexahydropyrylene-1-yl)propyl hydrazinyl hexahydroindenyl]-4-(2-methyl_ 3_丙冬基-味嗤-4-yl) pyrimidine_2_amine 1·49 (d,6H),1·57 (m,2H),1.91 (m5 2H)3 2.08 (m? 2H)? 2.22 (s, 3H), 2.38 (m, 10H), 2.50 (s, 3H), 2.93 (m, 4H), 3.70 (m, 2H), 3.90 (m, 1H), 4.88 (m, 1H), 5.46 (m, 1H), 6.69 (d5 1H), 7.24 (s, 1H), 8.14 (d5 1H) 505 120858 -71 - 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 7 4-(2-methyl -3-propan-2-yl-imidazol-4-yl)-N-[l-(3-norfosolin-4-ylpropylsulfonyl M-hexahydrop-indolyl)pyrimidin-2-amine 1·49 (d,6H), 1.57 (m, 2H), 1.92 (m, 2H), 2.09 (m, 2H), 2.38 (m, 6H), 2.50 (s, 3H), 2.93 (m, 4H) , 3.63 (m, 4H), 3.70 (m, 2H), 3.91 (m, 1H), 4.89 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 (d,1H) 492 8 2-[4-[3-[[4-[[4_(2-methyl-3-prop-2-yl).-4-yl)pyrimidin-2-yl] Amino]-1-hexahydropyridyl]sulfonyl]propyl]hexahydropyrrol-1-yl]ethanol 1.48 (d,6H) ,1·56 (m,2H),1.91 (m,2H),2.08 (m,2H),2.43 (m, 15H), 2.61 (s,1H), 2.93 (m,4H), 3.54 (m,2H) ), 3·70 (m, 2H), 3.90 (m, 1H), 4.89 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 ( d,1H) 535 Example 9 2-[3-[[4_[[4_(2-methyl-3-propan-2-yl- 嗤-4-yl) shouting -2_yl]amino]- 1-hexahydropyridyl]sulfonyl]propylamino]butan-1-ol in N-[l-(3-chloropropylsulfonyl)-4-hexayl which has been dissolved in THF (4 ml) Hydrogen bamboo (: dimethyl)-4-(2-methyl-3-propan-2-yl-salt-salt) sulphon-2-amine (example 3, 70 mg '0.16 mmol) solution, Sodium iodide (5 mg, 〇03 mmol) was added followed by 2-amino-1·butanol (〇·22 mL, 2.38 mmol). The reaction cake was heated by microwave irradiation at 150 ° C for 2 hours. The solvent was evaporated, and the formed material was purified by RPHPLC, which was modified by base. The material formed was dissolved in MeOH and added to a SCX-3 column pre-wetted with MeOH. The column was rinsed with MeOH and the product was eluted with 2M ammonia / MeOH. The solvent was evaporated to give a white solid (yield: 36 mg, 46%). NMR (400.132 MHz, CDC13) 0.85 (t, 3H), 1.30-1.49 (m, 8H), 1.57 (m5 2H), 1.91 (m5 2H), 2.08 (m, 2H), 2.47 (m, 4H), 2 · 63 (m, 1H), 2.80 (m, 1H), 2.95 (m5 4H), 3.24 (m, 1H), 3.56 (m, 1H), 3.70 (m, 2H), 3.91 (m, 1H), 4.92 (m,1H), 5.46 (m, 120858 -72- 200811169 1H), 6.69 (d,1H), 7.24 (s,1Η),8·14 (d,1H); MH+ 494. Examples 10-14 It was prepared by the procedure of Example 9 and using the appropriate amine starting materials on the same scale. Example compound NMR (400.132 MHz, CDC13) m/z 10 N-[l-[3-(l-methoxypropan-2-ylamino)propyl]indolyl]-4-hexahydrop ratio ]-4-(2-Methyl-3·propan-2-yl-amido-4·yl)- stilbidine-2-amine 0.94 (d, 3H), 1.49 (d, 6H), 1.56 (m, 2Η),1·90 (m,2Η),2·08 (m, 2H), 2·50 (s,3H), 2_68 (m,2H), 2.80 (m,1H),2·97 (m, 4H), 3.14 (m, 1H), 3.25 (m, 1H), 3.28 (s, 3H), 3J1 (m, 2H), 3.90 (m, 1H), 4.89 (m, 1H), 5·47 (m ,1H),6.69 (d,1H), 7.24 (s,1H),8·14 (d,1H) 494 11 propyl·2-yl·imisin-4-yl)pyrimidin-2-yl]amino] -1_ hexahydropyridyl] hydrazino] propylamino] propan-2-ol 1.09 (d, 3H), 1.49 (d, 6H), 1.57 (m, 2H), L92 (m, 2H), 2.09 (m , 2H), 2.36 (m, 1H), 2.50 (s, 3H), 2.70 (m, 3H), 2.95 (m, 4H), 3.71 (m, 3H), 3.91 (m, 1H), 4.92 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 (d, 1H) 480 12 2-[3-[[4-[[4-(2 Benzyl-3-propan-2-yl-imida-4-yl)pyrimidin-2-yl]amino]-1-hexamethyl 峨 定 定 ] 续 续 续 续 ] ] ] ] ] ] 399.902 MHz) 0.99 (d,3H),1_48 (d,6H),1.57 (m,2H),1.92 (m, 2H)5 2.08 (m5 2H)5 2.50 (s5 3H)5 2.61 (m,1H), 2.71 (m, 1H), 2.82 (m, 1H), 2.96 (m, 4H), 3.19 (m, 1H), 3.52 (m, 1H), 3·70 (m, 2H), 3.91 (m, 1H) , 4.93 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 (d, 1H) 480 13 3-mercapto-2-[3-[[4 -[[4-(2-methyl-3-propan-2-ylmiazole-4-yl)pyrimidin-2-yl]amino]-1-hexahydro sigma]sulfonyl]propylamino] Butan-1-ol 0.83 (d, 3H), 0.90 (d, 3H), 1.49 (d, 6H), 1.57 (m, 2H), 1.73 (m, 1H), 1.91 (m, 2H), 2.08 (m) , 2H), 2.31 (m, 1H), 2.50 (s, 3H), 2.63 (m, 1H), 2.80 (m, 1H), 2.95 (m, 4H), 3.27 (m, 1H), 3·55 ( m,1H), 3.71 (m, 2H), 3.91 (m, 1H), 4.91 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 (d , 1H) 508 120858 -73 · 200811169 Example compound NMR (400.132 MHz, CDC! 3) m/z 14 2-mercapto-2-[3-[[4-[[4-(2-methyl-3-) Propan-2-yl-imidazol-4-ylpyrimidin-2-yl]amino]-1-hexafluoroacetate -1-酉芋1.00 (s,6H), 1.49 (d,6H), 1.57 (m,2H),1.88 (m,2H),2.08 (m, 2H), 2.50 (s,3H), 2.60 (m , 2H), 2.96 (m, 4H), 3.23 (s, 2H), 3.70 (m, 2H), 3.91 (m, 1H), 4.92 (m, 1H), 5.46 (m, 1H), 6· 69 (d,1H), 7.24 (s,1H), 8.14 (d,1H) 494 Example 15 Ν·[1-[3·(2-Methoxyethylamino)propyl sulfhydryl]-4- Hexahydro-p-indenyl]-4-(2-methyl-3-propan-2-yl-miso-4_yl) shouts -2_amine in N- which has been dissolved in THF (3 ml) [l-(3-Chloropropylsulfonyl)-4-hexahydrop ratio 11 base]-4-(2·indolyl-3-propan-2-yl-flavor ti sit-4·yl) mouth In a solution of phospho-2-amine (Example 3, 42 mg, 0.09 mmol), sodium iodide (3 mg, 〇.〇 2 mmol) was added followed by 2-methoxyethylamine (〇·14) ML, 1.4 millimoles). The reaction was heated by microwave irradiation at 150 ° C for 2 hours. The reaction mixture was passed through and the filtrate was evaporated. The resulting material was dissolved in DCM and purified on silica gel eluting with 5% 2M ammonia / DCM in MeOH. The title compound was obtained as a yellow solid (36 mg, 79%). NMR (400.132 MHz, CDC13) 1.49 (d, 6H), 1.60 (m, 2H), 2·11 (m, 4H), 2.51 (s, 3H), 2·94 (m, 6H), 3.09 (m, 2H), 3.32 (s, 3H), 3.57 (m, 2H), 3.72 (m, 2H), 3.91 (m, 1H), 4.99 (m, 1H), 5.47 (m, 1H), 6.69 (d, 1H) ), 7.26 (s, 1H), 8.14 (d, 1H); MH+ 480. Example 16 3_[[4_[[4_(2_曱-yl-3-propan-2-yl-imidazolidyl)) Amino]sodium hexahydropyridyl]sulfonyl]propan-1-ol gives N-[l-(3-chloropropylsulfonyl) ice hexahydropyridyl]_4-(2-methyl- 3-prop-2-200858-74 - 200811169 m-sodium 4-yl) π pyridine 2 amine (example 3, 5 〇 mg, 〇ιι mmol) dissolved in the section (4 liters), added acetic acid Sodium (47 mg, 0.57 mmol) with sodium iodide (5 g, 0.03 mmol) and the reaction was heated by microwave irradiation for 1 hour at 14 Torr. The reaction mixture was filtered and washed with EtOAc. 2M NaOH (3 pens) was added to the filtrate and the solution was stirred at ambient temperature for 1 hour. The reaction solution was neutralized to a positive 7 with a 2M aqueous HCl solution, and solvent was evaporated. The formed substance KDCM was subjected to liquid separation treatment with water. The contents of the organic phase were purified on silica gel and eluted on a gradient of 5% to MeOH/DCM. The title compound was obtained as a yellow solid (17 mg, 36%). nmR (399 9〇2 MHz, CDC13) 1.55 (m, 8H), 1.7G (m, lH), 2.G5 (m, 4H), 2.5G (s, 3H), 2.93 (m, 2H), 3.02 (m, 2H), 3.73 (m, 4H), 3.90 (m, 1H), 4·91 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7·24 (s, 1H) ), 8.14 (d, 1H), MH+ 423· Example 17 4_[[4_(2-Mercapto-3-propan-2-ylimidazolyl-4-yl)-yl-2-yl]amino]hexahydropyridine Small sulfonamide to 4-(2-methyl-3-propan-2-yl-isoxazole)-N-(4-hexahydropyridyl)pyrimidin-2-amine in dioxane 2,60 mg, 0.2 mmol.) and decylamine (192 gram '2 house m') were heated under reflux for 16 hours. The reaction was cooled to ambient temperature and diluted with water (50 mL) EtOAc. The aqueous solution was extracted with DCM (5 X 50 mL). The combined organics were evaporated, and the obtained material was dissolved in EtOAc EtOAc (EtOAc) The title compound was obtained as a white solid (4 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NMR (400.132 MHz, CDC13) 1.49 (d,6H),1.61 (m,2H), 2.10 (m,2H),2·50 (s,3H),2_84 (m,2H),3·64 (m5 2H ), 3.88 (m, 1H), 4.39 (s, 2H), 4.96 (m, 1H), 5.48 (m, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8.14 (d, 1H) MH+ 380. Example 18 N,N-Dimethyl-4-[[4-(2_methyl_3_propan-2-ylimidazolyl-4-yl)acridin-2-yl]amino] Hydropyridine-1 _ decylamine dimethylamine sulfonium chloride (〇〇26 ml, 〇·24 mmol) in DCM (1 mL) was added dropwise to 4-(2-methyl-3) - propyl-2·yl^mazole base)-Ν-(4-hexahydropyridyl) chlorpyrifos-2-amine (Example 2; 60 mg, 〇·2 mmol) with TEA (0.084 ml) '0.66 mmoles in a stirred solution in DCM (1 mL). The solution was stirred at ambient temperature for 16 hours. Water (2 ml) was added, then the mixture was filtered through a PTFE cup and purified on silica gel eluting with a gradient of &lt After the development, and then evaporation, the compound was obtained as a colorless solid (62 ^: g, 76%). NMR (400.132 MHz, CDC13) 1.49 (d, 6H), 1.55 (m, 2H), 2.06 (m, 2H), 2·50 (S, 3H), 2.76 (S, 6H), 2·92 (m, 2H),3·62 (m,2H),3.88 (m,1H),4·88 (m,1H),5·49 (m,1H), 6.69 (d,1H),7.25 (s,1H) , 8.14 (d, 1H); MH+ 408. Example 19 4_[[4-(2-methyl-3-propan-2-yl-isoxazole-4-yl)pyrimidinyl]amino]hexahydropyridine Indoleamine 4-(2-methyl-3-propan-2-ylzirconazole)&gt;N_(4_hexahydropyridyl chlorinamide (Example 2; 150 mg, 0.5 mmol) Dissolve in THF (5 ml) and add a solution of potassium cyanate (163 mg, 2.0 mmol) in water (1 ml). Cool the solution formed from 120858-76-200811169 and add it to it and add 1 M HCl (2 mL). The reaction mixture was stirred at TC for 2 h then warmed to ambient temperature overnight. The reaction mixture was applied to 5 g of SCX-3 column with water (2×10 mL), Me〇H ( 2 X 10 ml) Wash, then dissolve in 3 · 5 3 3 〇 6 〇 11 (2 X 1 〇 ml). Remove the solvent in Zhenyu, obtain colorless colloid, develop it with ether, filter, sub-dry The title compound was obtained as a colorless solid ( 142 mg, 83%). NMR (400 MHz, CDC13) 1.44-1.59 (m5 8H)5 2.10 (d5 2H)5 2.57 (s5 3H), 3.02 (t5 2H)3 3.88 ^4.07 (m? 3H), 4.42 (brs, 2H)? 4.90-5.03 (m5 1H), 5.49-5.64 (m,1H), 6.75 (d,1H), 7.31 (s,1H), 8.21 (d, 1H) ; MH+ 344_ Example 20 N,N-Dimethyl_4_[[4-(2-methyl-3-propan-2-yl-oxazolyl)-yl-2-yl]amino] Nitrogen p to bite-1·Rebel amine to 4-(2•methyl-3-propan-2-yl-imidazolidinyl)_Ν_(4·hexahydropyridinyl)pyrimidine_2_amine (Example 2; 150 mg , 〇.5〇mmol) and ΤΕΑ (〇丨ml, 〇75mmol) dissolved in DCM (5ml). Add dimethylammonium chloride (〇.〇6ml), and The reaction was stirred under an inert atmosphere for 16 h. EtOAc (150 mg) was added and the mixture was stirred for one hour then filtered over a pad of celite and evaporated in vacuo. The title compound was obtained as a colourless solid (yield: 44 mg, 44%). NMR (4〇〇MHz) 1.39-1.57 (m,8H), L87 (d,2H), 2.48 (s,3H), 2.69-2.84 (m,8H),3.57 (d,2H),3·79- 3·93 (brs,1H), 5.74-6.54 (brs,1H), 6.80 (d,1H), 6.97-7.23 (brs,1H),7.34 (s,1H),8.12 (d, 1H) ; MH+ 372 Example 21 N-Methyl-4-[[4-(2-methyl-3-propan-2-yl-mycodazole) acridine:yl]amino]hexahydro 120858-77- 200811169 pyridine- The 1-carboxamide compound was subjected to the procedure of Example 109 and used in the same scale using 4-(2.methyl-3-propan-2-yl-oxazol-4-yl)-indole (4- Hexahydropyridyl) Mouthidine-2-amine (Example 2) was prepared as the starting material. NMR (CDC13) 2.19 (m,7Η), 2.27 (q, 1H), 2.49 (t,1H), 2.79 (s,3H), 2.82 (d,3H), 2.97 (dd,2H), 3.86-4.05 ( m, 3H), 4·46 (d, 1H), 5.04-5.24 (brs, 1H), 5.48-5.68 (m, 1H), 6.74 (d, 1H), 7.32 (s, 2H), 8.19 (d, 1H). Example 22 (4-methyl-1,4-diaza heptane small group)_[4_[[4-(2-methyl-3-propan-2-yl-carzol-4-yl) ), biti-2-yl]amino]-1-hexanitrogen p-bityl] formazan 4-nitrophenyl chloroantimonate (ill mg, 〇·55 mmol) was added under inert atmosphere. To 4-(2-indolylpropan-2-yl-oxazol-4-yl)-indole-(4-hexahydropyridyl)pyrimidin-2-amine (Example 2; 151 mg, 〇·5 mmol) Ears and hydrazine (0.15 ml, 1.10 mmol) in a stirred solution in dioxane (5 ml). After 2 hours, Ν-methyl homohexahydropyrone (0.069 g, 0.6 mmol) was added, and the reaction was heated at 80 ° C for 4 hours. The mixture was evaporated in vacuo and EtOAc EtOAc (EtOAc) The organic layer was dehydrated, filtered, and evaporated to give a solid. The residue was taken on a pad of EtOAc (EtOAc). NMR (CDC13, 400 MHz) 1.44-1.58 (m, 8H), 1.87-1.96 (m, 2H), 2.08 (d, 2H), 2.36 (s, 3H), 2.52-2.60 (m, 5H), 2.62 2.70 (m, 2H), 2.88 (t, 2H), 3·42-3·52 (m, 4H), 3_60 (d, 2H), 3.89-4.02 (m, 1H), 4·98 (brd, 1H) ), 5.51-5.67 (apparently broad, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8.20 (d, 1H); MH+ 120858 -78- 200811169 441. Examples 23-28 It was prepared by the procedure of Example 22, using the appropriate amine [?] at the same scale, and by RPHPLC. __ NMR (400.132 MHz, CDC13) m/z 23 N-(l-fluorenyl-4-hexahydrop-pyridyl)-4-[[4-(2-methyl-3-prop-2-yl) M. -4-yl) phen-2-yl]amino]hexahydropyridine-1-carboxyguanamine 1.41-1.58 (m,8H), 1.91-2.19 (m,6H),2·29 (s5 3H), 2.57 (s, 3H), 2·81 (d, 2H), 2.96 (t, 2H), 3.61-3.74 (m, 1H), 3.86-4.05 (m, 3H), 4.29 (d, 1H) , 4.96 (d, 1H), 5.49-5.67 (s, 1H), 6.75 (d, 1H), 7.31 (s, 1H), 8·20 (d, 1H) 441.6 24 N-[[(2S)-1 -ethyltetraapyridin-2-yl]methyl]-4-[[4-(2-methyl-3-prop-2-yl)-[n-[n]-[4-]-yl) ] Amino] hexahydro ρ to 17 -1- retinoin 1.09 (t, 4H), 1.40-1.78 (m, 12H), 1.79-1.93 (m, 1H), 2.07 (d, 2H), 2.12 2.30 (m, 2H), 2·57 (s, 3H), 2.58-2.68 (m, 1H), 2.72-2.86 (m, 1H), 2.97 (t, 2H), 3.17 (brd5 2H) 5 3.34-3.46 (m5 1H), 3.79-4.08 (m, 3H), 4.97 (d, 1H), 5.18-5.43 (brs, 1H), 5.50-5.65 (brs, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8.20 (d, 1H) 455.6 25 N-[[(2R)_1-ethyltetrahydrop-bi-2-yl]methyl]-4-[[4-(2-methyl-3-) Prop-2-yl_嗤-4-yl), butyl-2-yl]amino]hexahydropyridine-1-carboxyguanamine 1.09 (t5 4H), 1.40-1.78 (m, 10H), 1.79-1.93 (m, 1H), 2.07 (d, 2H), 2.12-2.30 (m, 2H), 2.57 (s, 3H), 2.58-2.68 (m, 1H), 2.72-2.86 (m, 1H), 2.97 (t, 2H), 3.17 (brd , 2H), 3.34-3.46 (m, 1H), 3.79-4.08 (m, 3H), 4.97 (appd, 1H), 5.18-5.43 (brs, 1H), 5.50-5.65 (brs, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8·20 (d, 1H) 455.6 26 N-(2-diamino-ethyl)ethyl [[4-(2-methyl-3-propyl) -2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]hexa-n-pyridinium carbarylamine 415.6 120858 -79- 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 27 [( 3S)-3_diammonium-tetrazinium-7bidol-1-yl] (2-methyl-3-propan-2-yl-σm. Sodium-4-yl) Mouth-2-yl]amino>&gt;1-hexahydro outside b σ-decyl] ketone 1.39-1.59 (m,8H), 1.69-1.81 (m,1H), 2.00-2.13 ( m,3H), 2.27(s,6H),2.57(s,3H),2.59-2.69 (m, 1H), 2.81-3.01 (m, 2H), 3.23 (t,1H), 3.40-3.58 (m, 3H), 3.73 (t, 2H), 3.93-4.05 (m, 1H), 4.99 (brd, 1H), 5.51-5.67 (brs, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8.20 (d,1H) 441.6 28 4-[[4-(2·methyl-3_propan-2-yl-oxazol-4-yl)pyrimidin-2-yl]amino]-Ν-(2-tetrahydrofluorene 17-1 -1 -ylethyl)hexahydropyridine carboxamide 1.41-1.58 (m,9H),1.74-1.81 (m,3H),2.03-2.11 (m,2H), 2·49-2_55 (m , 4H), 2.57 (s5 3H), 2.62 (t, 2H), 2.96 (t, 2H), 3.34 (q, 2H), 3.87-4.05 (m, 3H), 4.97 (d, 1H), 5.17-5.26 (brs, 1H), 5.49-5.64 (m, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8.21 (d, 1H) 441.6 Example 29 l-[4-[[4-(2- Methyl·3_propan-2-yl-isoxazole-based (tetra)pyridinyl]amino]pyrohydropyridinyl]ethanone 4-(2-methyl-3-propan-2-yl)carbazole Bucketin hexahydropyridyl (tetra)pyridine_2_amine (Example 2 '83 mg' 0.28 Monomolar suspension in DCM (2 mL). Add TEA (0.077 mL '0.55 mL), followed by acetic anhydride (0.03 mL, 0.30 mmol) in dCM (1 mL) over one minute. The reaction was stirred at ambient temperature for 3 d. EtOAc (EtOAc: EtOAc (EtOAc) M,,,,,,,,,, , 1H), 3·98 (m, 1H), 4.45 (m, 1H), 4.90 (m, 1H), 5.49 (m, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8.14 ( d,1H) ; MH+ 343· 120858 -80- 200811169 Example 30 l-[4-[[4-(2-Methyl-3-propanyl-imidazolidyl)pyrimidine:yl]amino]4 hexahydropyridine 4-(2-methyl-3-propan-2-yl-isoxazol-4-yl)-N- in DMF (2 ml) (4-Hexane 1^ &quot;定基) 哺 _2 _ 2 -amine (Example 2, 60 mg, 0.2 mmol), 4-morpholine-4-ylbutyrate (Method 3; 5〇 MG , 〇 24 mAh) 'HATU (91 gram, 0.24 mmol) and DIPEA (〇 14 ml, 〇 8 mmol), overnight at ambient temperature. The solvent was evaporated, and the formed material was partitioned between DCM (2 mL) and sat. The formed material was dissolved in dcm and purified on silica gel, and dissolved in a shallow gradient of 〇_1〇% Me〇H/DCM. The title compound was obtained as a white crystalline solid (64 mg, 70%). NMR (400.132 MHz, CDC13) 1.39 (m, 2H), 1.49 (d, 6H), 1.78 (m, 2H), 2·05 (m, 2H), 2.39 (m, 8H), 2.50 (s, 3H) , 2·78 (m, 1H), 3.12 (m, 1H), 3.65 (m, 4H), 3.82 (m, 1H), 3.98 (m, 1H), 4·45 (m, 1H), 4.89 (m , 1H), 5.49 (m, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8.14 (d, 1H); MH+ 456. Example 31 N_(l-methyl-4_hexahydro Pyridyl) 4-(2-methylpropan-2-yl-imidazolidine) 4-(2-methyl-3-propan-2-yl-isoxazol-4-yl)-N-( 4-Hexidopyridinyl) hydrazinamide (Example 2, 50 mg, 0.17 mmol) was dissolved in THF (2 mL). Add @曰 〇 (〇_〇1 ml, 017 mmol), Causes the precipitation of substances. Adding water to the water (37%, 1 liter) will cause the dissolved matter to dissolve. The anti-120858 -81 - 200811169 should be stirred at ambient temperature for 30 minutes. Add three Sodium bis oxyborohydride (100 mg), and the mixture was stirred for additional 2 hr. The solvent was evaporated and evaporated to sat. Filter, and add In a ruthenium tube column. The column was immersed in a shallow gradient of 0-20% of MeOH in MeOH / EtOAc. , 63%). NMR (400.132 MHz, CDC13) 1.52 (m, 8H), 2.01 (m, 4H), 2.23 (s, 3H), 2.50 (s, 3H), 2·76 (m, 2H), 3.75 (m, 1H), 4.90 (m, 1H), 5·57 (m iH) 6.65 (d, 1H), 7·24 (s, 1H), 8.12 (d, 1H); MH+ 315. Example 32 4_( 2-methyl-3-propan-2-yl-imidazole-4-yl) (1-propan-2-yl- 4-hexafluoropyridyl), pyridin-2-amine 4_mercapto 3·propyl-isazole _4_yl)-N-(4_hexahydropyridyl) σ-Bite _2 gastric amine (Example 2, 70 mg, 0·23 mmol) suspended in acetone (3 ml) )in. Acetic acid (0.013 mL, 0.23 mmol) was added followed by DCM (1 mL) to aid dissolution. The reaction was stirred at ambient temperature for 30 minutes. Sodium triethoxysulfonium borohydride (99 mg, 〇·47 mmol) was added and the reaction was left to stand for 16 hours. Further, sodium triethoxysulfonate (2 mg, 0.94 mmol) was added, and the reaction was heated at 40 ° C overnight. The solvent was evaporated, and the residue was neutralized with a saturated aqueous NaH.sub.3 solution, which was stirred with DCM and filtered through a PTFE cup. The DCM solvent was evaporated to give a clear oil. Ether was added and the solution was evaporated again. The title compound was obtained as a white solid (45 mg, 56%). NMR (400.132 MHz, CDC13) 0.98 (d,6H), 1.49 (m,8H), 1.99 (m,2H), 2.21 (m,2H), 2.50 (s,3H),2·67 120858 -82- 200811169 (m, 1H), 2.80 (m, 2H), 3.75 (m, 1Η), 4·91 (m, 1H), 5.57 (m, 1H), 6.64 (d, 1H), 7.24 (s, 1H), 8.12 (d,1H) ; MH+ 343. Example 33 4_(2_methyl-3-propan-2-yl- olmonyl)-N-(l-phenylethyl_4_hexahydrop-bite) 4-(2-methyl-3-propan-2-yl-isoxazole)-N-(4-hexahydropyridyl)-pyridoxamide in DMF (2 ml) (Example 2, 70 mg, 0.23 mmol), 2-bromoethylbenzene (65 mg, 0·35 mmol) and TEA (0·097 mL, 0·7 mmol) at 50 ° C Heat for 65 hours. The temperature was increased to 90 ° C for 2 hours and then the solvent was evaporated. The resulting material was dissolved in DCM and applied to EtOAc (EtOAc) elute The title compound was obtained as a white solid (33 mg, 35%). NMR (400.132 MHz, CDC13) 1.59 (m, 8H), 2.08 (m, 2H), 2·20 (m, 2H), 2.57 (s, 3H), 2·62 (m, 2H), 2·82 ( m,2H), 2.97 (m,2H),3·86 (m,1H),4.99 (m,1H), 5.63 (m,1H),6·72 (d,1H),7.21 (m,3H) , 7.29 (m, 3H), 8·20 (d, 1H); MH+ 405· Example 34 4-[[4-(2-methyl-3-propan-2-yl-oxazol-4-yl)pyrimidine -2-yl]amino]hexahydropyridine·1-carboxylic acid tert-butyl ester (2-methylpropan-2-yl)oxycarbonyl group which has been dissolved in THF (1 ml) - Butyl ester (44 mg, 0.2 mmol) was added to 4-(2-mercapto-3-propan-2-yl·oxazolidine)-Ν-(4-hexa) dissolved in thF (3 ml) Hydropyridyl)pyrimidine-2-amine (Example 2, 60 mg, 〇 2 mmol) solution. The reaction mixture was at 120858 -83 - 200811169

環境溫度下攪拌9G分鐘。蒸發溶劑，並使殘留物溶於DCM 中，且通過矽膠管柱，以〇_1〇% Me〇H/DCMi梯度液溶離。 合併含有產物之溶離份，並蒸發，獲得透明膠質。將醚添 加至該膠質中，並再蒸發，而得標題化合物，&amp;白色泡沫 物（47 毫克，59%)。nmR (4〇〇·132 讀2, CDCl3)】％ (m，iih)，工 48 ⑼ 6H)5 1.97 (m5 2H)? 2.50 (s? 3H)5 2.85 (m5 2H)? 3.93 (m? 3H), 4.88 (m5 1H)3 5.52 (m，1H)，6.67 (d，1H)，7.25 (s，1H)，8.13 (d，1H). 實例35 N-(l-乙烯基磺醯基-4-六氫吡啶基)_4_(2·甲基_3_丙_2_基-味唑_4_ 基）嘧啶-2-胺 將TEA(0·7毫升，5毫莫耳）添加至4_(2_甲基_3_丙_2_基_味唑 斗基）-N-(4-六氫吡啶基）喷啶么胺（實例2 ; 5〇〇毫克，17毫莫 耳）在DCM (25毫升）中之溶液内。將小體積之dcm中之氯化 2-氯乙烷磺醯（0.26毫升，2.5毫莫耳）逐滴添加至溶液中，獲 付從無色改變成黃色之顏色。在添加完成時，固體已形成。 3〇分鐘後，濾出固體物質。將濾液以DCM稀釋，並以水洗 務。以DCM萃取水相，並將合併之有機物質以鹽水洗務， 脫水乾燥，及蒸發。使所形成之物質溶於dcm中，並於矽 膠上層析，以0-10% MeOH/DCM之梯度液溶離。合併含有產 物之溶離份，及蒸發，而得標題化合物’為灰白色固體（218 毫克，34%)。MH+ 391. 實例36 Ν-[1-[2-(4-甲基六氫吡畊4-基）乙基磺醯基]冰六氫吡啶 基Η-(2-甲基各丙-2_基·喃峻-4·基）,咬_2-胺 120858 -84- 200811169 將1-甲基六氳吡畊（0.06毫升，〇·54毫莫耳）添加至N-(1_乙稀 基磺醯基-4-六氫吡啶基）冰(2-甲基各丙_2_基^米唑冬基）0密啶 -2-胺（實例35，72毫克，0.18毫莫耳）在丨：i THF/DCM (3毫升） t之溶液内。將反應混合物於環境溫度下攪拌72小時。蒸 發溶劑’並使所形成之物質藉由鹼修正之RPHPLC純化，產 生標題化合物，為膠質（60毫克，68%)。NMR (400.132 MHz， CDC13) 1_49 (d，6H)，1·56 (m，2H)，2.08 (m5 2H)，2.22 (s，3H)，2.39-2.46 (m，8H)，2_50 (s，3H)，2.77 (m，2H)，2·93 (m，2H)，3.06 (m，2H)，3.71 (m， 2H)，3.90 (m，1H)，4.88 (m，1H)，5.46 (m，1H)，6.69 (d，1H)，7·24 (s，1H)， 8.14 (d? 1H) ； MH+ 491. 實例37-62 下列化合物係藉由實例36之程序，並於相同規模下使用 適當胺起始物質製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 37 4-(2-甲基-3-丙-2-基-咪唑-4_基）-Ν·[1-(2-四 氣ρ比鳴^ -1-基乙基確* 蕴基）-4-六氫ρ比咬 基]喊啶_2-胺 1.48 (d，6H)，1.56 (m，2H)，1.74 (m，4H)，2.08 (m，2H)，2.48 (m， 7H)，2.85 (m，2H)，2.93 (m，2H)， 3.09 (m，2H)，3.71 (m，2H)，3.89 (m，1H)，4.88 (m，1H)，5·46 (m， 1H)，6.69 (d，1H)，7.24 (s，1H)， 8.14 (d，1H) 462 38 N-[l-[2-(2-甲氧基乙 胺基）乙基磺醯基]-4-六氫吡啶基]_4-(2-甲基-3-丙-2-基-口米嗤 -4-基）哺唆-2-胺 1·48 (d，6H)，1.57 (m，2H)，2.08 (m，2H)，2.50 (s，3H)，2.74 (m， 2H)，2.92 (m，2H)，3.05 (m，4H)， 3.29 (s，3H)，3.42 (m，2H)，3.71 (m，2H)，3·90 (m，1H), 4.89 (m， 1H)，5.46 (m，1H)，6·69 (d，1H)， 7.24 (s，1H), 8.14 (d，1H) 466 120858 -85 _ 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 39 4-(2-曱基-3-丙-2-基_ 咪唑-4-基）-Ν·[&gt;(2-硫 代嗎福琳-4-基乙基 石黃酿基）-4-六氣Ρ比σ定 基]嘧啶-2-胺 1.49 (d，6H)，1·57 (m，2H)，2·09 (m，2H)，2.52 (s，3H)，2·61 (m， 4H)，2·70 (m，4H)，2·81 (m，2H)， 2.93 (m，2H)，3.04 (m，2H)，3·70 (m，2H)，3.91 (m，1H)，5.00 (m， 1H)，5.45 (m，1H)，6.69 (d，1H)， 7.26 (s，1H)，8.15 (d，1H) 494 40 4-(2-甲基-3-丙-2-基_ 咪峻-4-基）-N-〇[2-(l-六氫说σ定基）乙基石黃 酿基]-4-六鼠ρ比ϋ定 基]喊唆-2-胺 476 41 N-[l-[2-(曱基-丙-2-基 -胺基）乙基磺醯基]-4-六氫ρ比咬基]-4-(2-甲基-3-丙-2-基-。米°坐 -4-基）,淀_2_胺 0.97 (d，6H)，1.53 (m，8H)，2.09 (m，2H)，2·17 (s，3H)，2.50 (s， 3H)，2.79 (m，3H)，2.91 (m，2H)， 3.02 (m，2H)，3.72 (m，2H)，3.89 (m，1H)，4.89 (m，1H)，5.47 (m， 1H)，6.69 (d，1H)，7.24 (s，1H), 8.14 (d, 1H) 464 42 N-[l-[2-(氮四園-1-基）乙基續酿基]-4· 六氫吡啶基]-4-(2-甲 基-3-丙-2-基-哺0坐-4· 基）嘧啶-2-胺 448 43 4-(2-甲基-3-丙-2-基-咪唑-4·基）-Ν-[1·(2-嗎 福啉-4-基乙基磺醯 基）-4-六氫吡啶基] p密咬-2-胺 478 44 N-[l-[2-(4•甲基小六 氫吡啶基）乙基磺醯 基M-六氫？比σ定基]-4-(2_曱基；丙-2-基-味 唑-4_基）嘧啶-2-胺 0.87 (d，3H)，1.18 (m，2H)，1.31 (m，1H)，1.48 (d，6H)，1.56 (m， 4H)，1.99 (m，2H)，2.08 (m，2H)， 2.50 (s，3H)，2.77 (m，4H)，2·93 (m，2H)，3.08 (m，2H)，3.71 (m， 2H)，3.90 (m, 1H)，4.90 (m，1H)， 5.46 (m，1H)，6.69 (d，1H)，7.24 (s，1H)，8.14 (d，1H) 490 120858 -86- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 45 N-〇[2-(—氮七圜烷 -1-基）乙基石黃酿基]-4-六氮p比σ定基]-4-(2-甲 基-3·丙-2-基 基）嘴唆-2-胺 490 46 N-[l-(2-二乙胺基-乙 基績酸基）-4-六氮p比 σ定基]-4-(2·曱基-3-丙 -2_基-味嗤-4-基）σ密咬 2-胺 464 47 4-[2-[[4-[[4-(2·曱基-3-丙-2-基米吐-4-基）σ密 唆-2-基]胺基]-1-六鼠 外匕σ定基]績醢基]乙 基]六氫ρ比畊-2-酮 1.49 (d，6H)，1.58 (m，2H)，2.09 (m，2Η)，2.50 (s，3Η)，2.67 (m， 2H)，2.87 (m，2H)，2.95 (m，2H)， 3.06 (m，2H)，3.12 (s，2H)，3.32 (m，2H)，3.70 (m，2H)，3.92 (m， 1H)，5.04 (m，1H)，5.45 (m，1H)， 5.93 (s，1H)，6.69 (d，1H)，7.25 (s，1H)，8_14 (d，1H) 491 48 4-(2-甲基-3-丙-2-基_ 口米峻-4- 基)-N-[l-[2-(l，4-氧氮 七圜-4-基）乙基磺醯 基]-4-六氮此σ定基] 嘧啶-2-胺 492 49 N-[l-[2-[(3R)-3-氟基四 氫吡咯-1·基]乙基磺 酿基]-4-六氮^比σ定 基]-4-(2-甲基-3-丙-2-基-咪唑斗基）嘧啶-2-胺 480 50 N-[l-[2-(4_ 氟基-1-六 氫外b唆基）乙基確醯 基]-4-六氫峨咬基]-4-(2-甲基-3_丙-2-基-口米嗤-4-基）β密咬-2-胺 494 120858 -87- 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 51 Ν_[1-[2-(7-氮雙環并 [2.2.1]庚-7-基）乙基磺 醯基]-4-六氫咐σ定基]-4-(2-甲基-3-丙-2-基_ 咪唑-4-基）嘧啶-2-胺 488 52 N-[l-[2-(環丙基-甲基 -胺基）乙基續酿基]-4-六氮外b σ定基]-4-(2-甲基-3-丙-2-基-咪唑 -4_基）ϋ密σ定-2-胺 462 53 Ν-[1-ρ·(環丙基甲基-甲基-胺基）乙基績 酿基]-4-六鼠ρ比17定 基]-4-(2-甲基-3-丙-2_ 基-咪唑-4-基）嘧啶-2-胺 476 54 1-[2-[[4-[[4-(2-甲基-3-丙-2-基/乐ϋ坐-4-基）口密 咬-2-基]胺基]-1-六氫^： ϋ定基]績醯 基]乙基]六氫吡啶 -4-羧醯胺 1·49 (d，6H)，1·59 (m，2H)，1·70 (m，2H)，1.84 (m，2H)，2.07 (m5 5H)，2.50 (s，3H)，2.75 (m，2H)， 2.87 (m，2H)，2.96 (m，2H)，3.06 (m，2H)，3.68 (m，2H)，3.92 (m， 1H), 4.93 (m，1H)，5.21 (m，1H)， 5.46 (m，2H)，6·69 (d，1H)，7.24 (s，1H)，8.13 (d，1H) 519 55 1-[4-[2-[[4-[[4-(2-甲基 -3-丙-2-基-味°坐-4-基） 口密σ定-2-基]胺基]-1-六 氫外b σ定基]績醯基] 乙基]六氮说11井-1-基]乙酮 519 56 1-[2-[[4-[[4-(2-甲基-3-丙-2-基-ρ米唆-4-基）, σ定-2-基]胺基]-1-六鼠 叶匕σ定基]磺醢基]乙 基]-1，4-二氮七圜烷 -5-酉同 1.48 (d，6H)，1.58 (m，2H)，2.09 (m，2H)，2.50 (s，3H)，2.60 (m， 6H)，2.92 (m，4H)，3.03 (m，2H)， 3.24 (m，2H)，3.69 (m，2H)，3.92 (m，1H)，5.01 (m，1H)，5.45 (m， 1H)，5.86 (m，1H)，6.69 (d，1H)， 7.25 (s，1H)，8.14 (d，1H) 505 120858 -88 - 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 57 1-[4·[2-[[4-[[4-(2-甲基 -3-丙-2-基-π米唾-4-基） 口密σ定-2-基]胺基]-1-六 氫叶b唆基]續酸基] 乙基]-1，4-二鼠七固 烧-1-基]乙酉同 533 58 4-(2-曱基-3-丙-2-基_ 咪唑-4-基）-Ν-[1·[2-(4- 丙基-1-六鼠ρ比σ定基） 乙基績酿基]-4-六鼠 外匕σ定基]喊唆-2-胺 518 59 4-(2-甲基-3-丙-2-基-咪唑-4-基）-N-[l-[2-(1，4-硫氮七圜-4-基） 乙基石黃酿基]-4-六氮 外匕σ定基]嘴唆-2-胺 508 60 N-[l-[2-(2-氮雙環并 [2·2·2]辛-2-基）乙基磺 酿基]-4-六鼠批σ定基]-4-(2-甲基-3·丙-2-基-口米峻-4-基密咬-2-胺 502 61 1-[2-[[4-[[4-(2-甲基-3-丙-2-基-味°坐-4-基）°密 °定-2-基]胺基]-1-六鼠 吡啶基]磺醯基]乙 基]六氮峨°定-4-甲赌 501 62 N-[H2-[(3S)-3-氟基四 氮外b洛基]乙基石黃 酿基]-4-六氮说σ定基]-4-(2-曱基-3-丙-2-基_ 口米唾-4-基）u密咬-2-胺 480 實例63 4-(2-甲基各丙-2·基·咪唑-4-基）-Ν-(1·甲磺醯基-4-六氫吡啶基） 120858 -89- 200811169 嘧啶-2-胺 將2-氯基-4-(2-甲基各丙-2-基-咪唑斗基）嘧啶（方法5 ; 105毫 克，0.44毫莫耳）、1-甲磺醯基六氫吡啶-4-胺TFA鹽（實例162， W004/069139，156 毫克，0.53 毫莫耳）、DIPEA (0.23 毫升，1.33 毫莫耳）及IPA (3毫升）合併，並在140°C下，藉由微波照射加 熱30分鐘。使反應混合物通過聚合體所承載之重碳酸鹽藥 筒，然後於140°C下再加熱30分鐘。使另一份1-曱磺醯基六 氫吡啶-4-胺 TFA 鹽（實例 162，W004/069139，220 毫克，0.76 毫莫耳）溶於MeOH中，並添加至被MeOH預潤濕之SCX-2管 柱中。將管柱以MeOH沖洗，且自由態鹼係以MeOH中之2M 氨溶離。蒸發溶離劑，並將所形成之物質添加至DIPEA (0.2 毫升）中作成溶液之反應物中。將反應物於15〇°C下加熱5小 時。藉過濾收集所形成之沉澱物，溶於DCM中，且於矽膠 上純化，以10% MeOH/DCM溶離。使得自反應物之濾液蒸發， 溶於DCM中，及於矽膠上純化，在0-5% MeOH/DCM，接著5% MeOH/DCM之淺梯度液上溶離。將得自兩個管柱之含有所需 要產物之溶離份合併，並蒸發，而得標題化合物，為白色 固體。（70 毫克，42%)。NMR (400.132 MHz) 1.55 (d，6H)，1.64 (m，2H)， 2.03 (m，2H)，2·53 (s，3H)，2.88 (m，2H)，2·94 (s，3H)，3.64 (m，2H)，3.89 (m，1H)，5·67 (m，1Η)，6·87 (d，1H)，7.20 (s，lH)，7.40 (s，1H)，8.27 (d， 1H) ； MH+ 379. 實例64 4-[[4-(2-甲基-3-丙-2-基-味嗤-4-基）喊咬-2-基]胺基】六氮p比咬 羧酸乙酯 120858 -90- 200811169 將2-氯基-4-(2-甲基-3-丙-2·基-味唑-4-基）哺啶（方法5 ; 70毫 克’ 0·3宅莫耳）、4-胺基-1-六氫ρ比σ定緩酸乙醋（1〇3毫克，0.6 毫莫耳）、TEA (0.084毫升，0.6毫莫耳）及ΙΡΑ (3毫升）合併， 並在160°C下，藉由微波照射加熱5小時。蒸發溶劑；使殘 留物溶於DCM中，並以水洗滌，經過ptfE杯過濾，且蒸發 溶劑。使所形成之物質藉由鹼修正之RPHPLC純化，而得標 題化合物，為白色固體（52毫克，46%)。NMR (400.132 MHz， CDC13) 1.20 (t，3H)，1.38 (m，2H)，1.49 (d，6H)，1·99 (m，2H)，2.50 (s，3H)， 2.91 (m，2H)，3·91 (m，1H)，4.07 (m，4H)，4.89 (m，1H)，5·51 (m，1H)，6·68 (d，1H)，7.25 (s，1H)，8.14 (d，1H) ; MH+ 373· 實例65 内向-8_甲基甲基-3_丙：基哺唑_4-基）嘧啶-2-基】·8-氮 雙環并[3·2·1]辛-3_胺 將2-氣基-4-(2-甲基-3-丙-2-基-味唆-4-基）哺咬（方法5 ; 70毫 克，〇·3毫莫耳）、内向-8-曱基各氮雙環并[3·2·1]辛-3-胺二鹽酸 鹽（128毫克，0.6毫莫耳）、ΤΕΑ(0·25毫升，1.8毫莫耳）及ΙΡΑ(3 毫升）合併，並在160°C下，藉由微波照射加熱8小時。蒸發 溶劑；使殘留物溶於DCM中，並以水萃取。將水相添加至 SCX-3管柱中，其已預先被MeOH濕潤。將管柱以MeOH沖洗， 且產物係以MeOH中之2M氨溶離，及蒸發溶離劑。使所形 成之物質藉由鹼修正之RPHPLC純化，而得標題化合物，為 白色固體（10 毫克，10%)。NMR (400.132 MHz，CDC13) 1.46 (d，6H)， 1.75 (m，2H)，1.87 (m5 2H)，2.08 (m，2H)，2.23 (m，5H)，2·49 (s，3H)，3·13 (m，2H)，4·05 (m，1H)，5.33 (m，1H)，5.64 (m，1H)，6.67 (d，1H)，7·26 (s， 120858 -91 - 200811169 1H)，8.11 (d，1H) ; MH+ 341. 實例66 N-[l-(2-甲氧基乙基）冬六氫吡啶基】·4·(2_甲基各丙_2基味唑 •4-基）嘧唆-2_胺 將2-氯基-4-(2-甲基-3-丙-2-基·味唑冰基）嘧啶（方法5 ; 70毫 克’ 0.3毫莫耳）、；u(2_甲氧基乙基）六氫吡啶_4_胺（95毫克， 〇·6毫莫耳）、TEA (0.084毫升，0.6毫莫耳）及IPA (3毫升）合併， 並在160 C下’藉由微波照射加熱5小時。蒸發溶劑；使殘 留物溶於DCM中，並以水洗滌，經過PTFE杯過濾，且蒸發 溶劑。使所形成之物質藉由鹼修正之ppjjpLC純化，而得標 題化合物’為膠質（34 毫克，32%)。NMR (400.132 MHz，CDC13) 1.49 (d，6H)，1.56 (m，2H)，1·98 (m，2H)，2.12 (m，2H)，2.52 (m，5H)，2.87 (m，2H)，3.29 (s，3H)，3.45 (m，2H)，3.77 (m，1H)，4.90 (m，1H)，5.56 (m， 1H)，6.65 (d，1H)，7.24 (s，1H)，8·12 (d，1H) ; MH+ 359· 實例67 甲基-3-丙-2-基-喷唑-4-基）_N-(1_丙基-4-六氫吡啶基）喊啶 -2-胺 將2-氯基-4·(2·甲基_3-丙-2-基味唑-4-基 &gt;密唆（方法5 ; 70毫 克’ 〇·3毫莫耳）、1-丙基六氫吡啶—4-胺（85毫克，0.6毫莫耳）、 TEA (0.084毫升，〇·6毫莫耳）及ΙΡΑ (3毫升）合併，並在i6(rc 下’藉由微波照射加熱5小時。蒸發溶劑，並使殘留物溶於 DCM (10毫升）中，且以水（1〇毫升）洗滌，然後經過pTFE杯 過渡’及蒸發DCM層。使所形成之物質溶於DCM中，並於 矽膠上純化，以〇_5〇/。2M氨在MeOH/DCM中之梯度液溶離。 120858 -92· 200811169 將含有純產物之溶離份合併’並蒸發’而得標題化合物， 為白色固體（45 毫克，44%)。NMR (400.132 MHz，CDC13) 0.84 (t， 3H)，1.47 (m，10H)，2.01 (m，4H)，2.23 (m，2H)，2.50 (s，3H)，2.82 (m，2H)， 3.76 (m，1H)，4.90 (m，1H)，5.58 (m，1H)，6.65 (d，1H)，7.24 (s，1H)，8.12 (d，1H) ; MH+ 343· 實例68 4-[2-[4_[[4·(2_甲基-3-丙_2-基-味嗤-4_基）,咬-2-基]胺基】-1-六氮 口比咬基]嗣基-乙基】六乳峨咬_1_叛酸第三-丁醋 將4-(2-曱基-3-丙-2-基-味嗤-4_基）-N-(4-六氫π比唆基）癌π定_2-胺（實例2，100毫克，0.33毫莫耳）、1-((1，1_二曱基乙氧基） 羰基)-4-六氫咐咬醋酸（97毫克，0.4毫莫耳）、HATU (152毫克， 〇·4毫莫耳）、DIPEA (0.23毫升，1·33毫莫耳）及DMF (4毫升） 合併，並於環境溫度下攪拌過夜。蒸發溶劑，並使所形成 之物質於DCM (2毫升）與飽和NaHC03水溶液（2毫升）之間作 分液處理，經過PTFE杯重力過濾，及蒸發。使所形成之物 質溶於DCM中，並於矽膠上純化，以〇_5% Me〇H/〇CM之淺梯 度液溶離。將含有純物質之溶離份合併，並蒸發，而得標 題化合物（23 毫克，13%)。NMR (400.132 MHz，CDC13) 1.07 (m，2H)， 1·37 (m，11H)，1.49 (d，6H)，1.68 (m，2H)，1.94 (m，1H)，2.05 (m，2H)，2.20 (m，2H)，2_51 (s，3H)，2.67 (m，2H)，2.78 (m，1H)，3·11 (m，1H)，3·80 (m， 1H)，4.00 (m，3H)，4.47 (m，1H)，4·88 (m，1H)，5.48 (m，1H)，6.69 (d，1H)， 7.25 (s，1H)，8.15 (d，1H) ; MH+ 526. 實例69-79 下列化合物係藉由實例68之程序，並於相同規模下使用 120858 -93- 200811169 適當酸起始物質製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 69 4-[3-[4-[[4-(2-甲基-3-丙-2-基-味°坐-4-基）口密 咬-2-基]胺基]-1-六氣 ^比σ定基]-3-S同基-丙 基]六氫说啡-1-鲮酸 第三-丁酯 1.37 (m，11H)，1.49 (d，6H)，2.05 (m，2H)，2.37 (m，4H)，2_48 (m， 5H)，2.67 (m，2H)，2·78 (m，1H)， 3.12 (m，1H)，3.36 (m，4H)，3·80 (m，1H)，3·98 (m，1H)，4·44 (m， 1H)，4·87 (m，1H)，5·48 (m，1H)， 6.69 (d，1H)，7.25 (s，1H)，8·14 (d，1H) 541 70 4-[3-[4-[[4-(2-甲基-3-丙-2-基-ϋ米嗤-4-基）口密 淀-2-基]胺基]-1-六氯 吡啶基]-3-酮基-丙 基]六氫吡啶小羧酸 第三-丁酯 1.05 (m，2H)，1·38 (m，12H)， 1.52 (m5 8H), 1.61 (m, 2H)5 2.05 (m，2H)，2.30 (m，2H)，2.51 (s， 3H)，2.61 (m，2H)，2.78 (m，1H)， 3_11 (m，1H)，3.78 (m，1H)，4.00 (m，3H)，4.45 (m，1H)，4.98 (m， 1H)，5.49 (m，1H)，6.69 (d，1H)， 7.26 (s，1H)，8.15 (d，1H) 540 71 4-甲基冰[4-[[4-(2-甲 基-3-丙-2·基-口米嗤-4-基）嘧啶-2-基]胺基] 六氛批咬-1-幾基]六 氫外1：咬小魏酸第三-丁酯 1.23 (s，3H)，1.40 (m，13H)，1.50 (d，6H)，2.06 (m，4H)，2.51 (s， 3H)，2.96 (m，2H)，3.17 (m，2H)， 3·58 (m，2H)，4.00 (m，1H)，4.26 (m，2H)，4·90 (m，1H)，5.49 (m， 1H)，6.69 (d，1H)，7·26 (s，1H)， 8.15 (d? 1H) 526 72 (3S)-3-[2_[4-[[4-(2-甲基 •3-丙-2-基-ϋ米。坐-4_基） 0密σ定-2-基]胺基]小六 氮0比σ定基]-2-嗣基-乙基]六風ι ρ比σ定-1-竣 酸第三-丁酯 U6 (m，1H)，1·38 (m，12H)， 1·49 (d，6H), 1.56 (m，1H)，1.82 (m，1H)，2.06 (m，4H)，2.25 (m， 1H)，2.51 (s，3H)，2.63 (m，1H)， 2.80 (m，2H)，3.11 (m，1H)，3.76 (m，3H)，3.98 (m，1H)，4.47 (m， 1H)，4.90 (m，1H)，5.49 (m，1H)， 6·69 (d，1H), 7.25 (s，1H)，8.15 (d，1H) 526 120858 94- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 73 (3R)-3-[2-[4-[[4-(2-甲基 -3-丙_2-基-喃°坐-4-基） 嘧啶-2_基]胺基]小六 氮？比σ定基]-2-嗣基-乙基]六氣p比17定**1-竣 酸第三-丁酯 1.16 (m，1H)，1.38 (m，12H)， 1.49 (d，6H)，1.57 (m，1H)，1.82 (m，1H)，2.05 (m，4H)，2.25 (m， 1H)，2.51 (s，3H)，2.62 (m，1H)， 2.79 (m，2H)，3.11 (m，1H)，3.76 (m，3H)，3_98 (m5 1H)，4.47 (m5 1H)，4.89 (m，1H)，5.49 (m，1H)， 6.69 (d，1H)，7.25 (s，1H)，8.15 (d，1H) 526 74 2-二甲胺基 _1-[4-[[4-(2-甲基-3-丙-2-基·口米 吐-4-基）♦ σ定-2-基]胺 基]-1-六氣ρ比咬基] 乙酮 (DMSO) 1·37 (m，2H)，1.50 (d， 6H)? 1.91 (m5 2H)5 2.20 (s5 6H), 2·70 (m，1H)，3·09 (m，3H)，3.93 (m，1H)，4.07 (m，1H)，4.31 (m， 1H)，5·13 (m，1H)，6·80 (d，1H)， 7·12 (寬廣 s，1H)，7.35 (s，1H)， 8.20 (d，1H) 386 75 3-二曱胺基-1-[4-[[4-(2-甲基-3-丙-2-基·咪 唑-4-基）嘧啶-2-基]胺 基]-1-六氫ρ比σ定基] 丙-1-晒 (DMSO) 1·49 (m，2H)，1.50 (d， 6H)，1.81 (m，2H)，2.44 (s，3H)， 2.63 (m，1H)，2.72 (m，1H)，2.83 (m，1H)，3.11 (m5 1H)，3.92 (m， 2H)，4.33 (m，1H)，5.62 (m，1H)， 6.81 (d，1H)，7·16 (寬廣 s，1H)， 7·37 (s，1H)，8.21 (d，1H) 400 76 4-二甲胺基-1-[4-[[4-(2-甲基-3_丙-2-基-味 唑4-基）嘧啶-2-基]胺 基]-1-六氫叶b ϋ定基] 丁 -1-酮 (DMSO) 1.39 (m，2H)，1.51 (d， 6H)，1.84 (m，2H)，1·93 (m，2H)， 2.42 (m，2H)，2.54 (s，3H)，2.79 (s，6H)，3_08 (m，2H)，3.12 (m， 1H)，3.86 (m，1H)，3·99 (m，1H)， 4·32 (m，1H)，5.62 (m，1H), 6.83 (d，1H)，7.23 (寬廣 s，1H)，7.51 (s，1H)，8.27 (d，1H) 414 77 (1-甲基-3-六氫ρ比唆 基）-[4-[[4-(2-曱基-3-丙-2-基-η米嗤-4-基）嘴 σ定-2_基]胺基]小六氫 叶匕σ定基]甲嗣 1.44 (m，3H)，1.57 (s，6H)，1.78 (m，2H)，2·13 (m，4H)，2.36 (s， 3H)，2.58 (s，3H)，2.87 (m，4H)， 3.20 (m，1H)，3·95 (m，1H)，4.07 (m，1H)，4.52 (m，1H)，4.96 (m， 1H)，5.57 (m，1H)，6.77 (d，1H)， 7.31 (s，1H)，8·21 (s，1H) 426 120858 -95- 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 78 [4-[[4-(2-曱基-3-丙-2_ 基-咪唑冰基）嘧啶·2_ 基]胺基]小六氫Ρ比 唆基Hi-甲基四氫 吡咯-2-基）甲酮 1.43 (m5 2H)，1.55 (d，6Η)5 1·62 (m，2H)，L86 (m，4H)，2.10 (m， 2H)，2.22 (m，1H)，2.38 (s，3H)， 2.56 (s，3H)，2·86 (m，1H)，3.08 (m，1H)，3.15 (m，2H), 4.11 (m， 2H)，4.54 (m，1H)，4.97 (m，1H)， 5·57 (m，1H)，6.77 (d，1H)，7.32 (s，1H)，8.21 (d，1H) 412 79 2-[4-[[4-(2-甲基-3-丙 -2-基』米β全-4_基）哺π定 -2-基]胺基]六氫υ比 啶小羰基]嗎福啉斗 羧酸第三-丁酯 1.45 (s，9H)重疊 1.45 (m，2H)， 1·54 (d，6H)，2·12 (m，2H)，2.57 (s，3H)，3.00 (m，1H)，3.18 (m， 2H)，3.53 (m，2H)，3.90 (m，2H)， 4.07 (m，2H)，4.48 (m，1H)，4.96 (m，1H)，5.55 (m，1H)，6.76 (d， 1H)，7_31 (s，1H)，8.20 (d，1H) 514 實例80 1·【4_[[4-(2•甲基_3-丙_2_基-咪唑-4-基）痛啶_2_基]胺基】小六氫吡 咬基】-2-(4-六氮〃比咬基）乙綱 使4-[2-[4_[[4-(2-甲基-3-丙-2-基味唑-4-基）。密淀-2-基]胺基]小 六氫吡啶基]-2-酮基-乙基]六氫吡啶小羧酸第三_丁 g旨（實例 68，〜170毫克，0.33毫莫耳）溶於DCm (3毫升）中，並添加等 體積之TFA。將反應物於環境溫度下攪拌3小時，然後添加 至被MeOH (2個管柱體積）預潤濕之5克SCX-3管柱中。使管 柱以MeOH (2個管柱體積）溶離，且產物係以Me〇H中之2M 氨溶離。蒸發鹼性溶離劑，而得標題化合物，為玻璃態物 質（46 毫克，27%)。NMR (500.133 MHz) 1.10 (m5 2H)，1.44 (m，2H)， 1·51 (d，6H)，1·62 (m，2H)，L81 (m，1H)，1.93 (m，2H)，2.22 (m，2H)，2.47 (s，3H)，3·99 (m，1H)，4·10 (m，1H)，5·58 (m，1H)，6·62 (d，1H)，6·76 (d， 1H)，7.28 (s，1H)，8.19 (d，1H) ; MH+ 426. 120858 -96 - 200811169 實例81-85 工列化合物係藉由實例8〇之程序，並於相同規模下製成。 賞例 化合物 i/g 〜α 4曰1 NMR (500.133 MHz) 口j 俠 m/z SM 一 81 H4-[[4-(2-甲基各 丙-2-基-口米σ坐-4-基）嘧啶-2_基]胺 基]小六氫外I：咬 基]-3-六氫ρ比畊 小基-丙-Ι-g同 1.46 (m，2H)，1.51 (d， 6H)，1.93 (m，2H)，2.33 (m，4H)，2.47 (m，5H)， 2.55 (m，2H)，2.70 (m， 4H)，3.98 (m5 1H)，4_09 (m，1H)，5.58 (m，1H)， 6.62 (d，1H)，6.76 (d， 1H)，7.28 (s，1H)，8.19 (d，1H) 441 實例69 82 1 -[4-[[4-(2-甲基-3-丙-2-基-^米嗤-4-基）嘧啶-2-基]胺 基]-1-六鼠ρ比咬 基]-3-(4-六鼠口比 17定基）丙-U同 1.03 (m，2H)，1.35 (m， 1H)，1.47 (m，4H)，1.51 (d，6H)，1.61 (m，2H)， 1.93 (m，2H)，2.31 (m， 2H)，2·47 (s，3H)，3.98 (m，1H)，4.09 (m，1H)， 5.58 (m，1H)，6.62 (d， 1H)，6.76 (d，1H)，7.28 (s，1H), 8.19 (d，1H) 440 實例70 83 (4-曱基-4-六鼠p比 啶基 H4-[[4-(2-甲 基-3-丙-2-基-口米 〇坐-4-基）°密σ定_2-基]胺基]-1-六氫 吡啶基]甲酮 1.29 (s，3H)，1.47 (m， 2H), 1.50 (d，6H)，1.65 (m，2H)，1.96 (m，2H)， 2.21 (m，2H)，2.47 (s， 3H)，3.00 (m，4H)，3.15 (m，2H)，4.02 (m，1H)， 4.19 (m5 2H)? 5.54 (m5 1H)，6.76 (d，1H)，7.28 (s，1H)，8.19 (d，1H) 426 實例71 120858 97- 200811169 實例 化合物 NMR (500.133 MHz) m/z SM 84 H4-[[4-(2-甲基-3-丙-2-基·。米唾-4-基）嘧啶_2_基]胺 基六氫峨咬 基]_2-[(3S)各六氫 吡啶基]乙酮 1.25 (m，1H)，1.46 (m， 2H)，1·50 (d，6H)，1·66 (m，1Η)，1.80 (m，2Η)， 1.94 (m，2H)，2.19 (m， 1H)，2.33 (m，2H), 2.47 (s，3H)，2.61 (m，1H)， 2·76 (m，1H)，3.19 (m， 1H)，3·27 (m，1H)，3·99 (m，1H)，4.09 (m，1H)， 5.55 (m，1H)，6.77 (d， 1H)，7·28 (s，1H)，8.19 (d，1H) 426 實例72 85 1·[4-[[4-(2-曱基-3-丙-2-基米唾-4-基）哺σ定-2-基]胺 基]-1-六氫巧1： σ定 基]-2-[(3R)-3-六氫 吡啶基]乙酮 1.25 (m，1H)，1·46 (m， 2H)，1.50 (d，6H)，1.66 (m，1H)，1.80 (m，2H)， 1.94 (m，2H)，2·19 (m， 1H)，2·33 (m，2H)，2·47 (s，3H)，2.62 (m，1H)， 2.77 (m，1H)，3.19 (m， 1H)，3.28 (m，1H)，3.99 (m，1H)，4.09 (m，1H)， 5.55 (m，1H)，6.77 (d， 1H)，7.28 (s，1H)，8.19 (d，1H) 426 實例73 實例86 [4_[[4-(2_甲基-3-丙-2_基·味唑-4-基）喊啶-2-基】胺基】-1_六氩吡啶 基】-嗎福V林-2-基-甲嗣 將二氧陸圜中之4M HC1 (4毫升）添加至2-[4-[[4·(2-甲基-3-丙 -2-基-咪唑-4-基）痛啶-2-基]胺基]六氫吡啶_1_羰基]嗎福啉-4遵 酸第三-丁酯（實例79 ; 〇·3克，0.58毫莫耳）在DCM (4毫升）中 之溶液内。在攪拌16小時後，添加2Μ NaOH，以調整至pH 12，並將水層以DCM (3 X 15毫升）萃取。使合併之有機物質 脫水乾燥，過濾，及在真空中濃縮，獲得無色泡沫物。於 120858 -98- 200811169 矽膠上藉急驟式層析純化，以DCM中之〇至10% MeOH溶 離，獲得標題化合物，為無色泡沫物（〇·19克，79%)。NMR (CDC135 400.132 MHz) 1.46 (m5 2H)5 1.56 (d, 6H)5 2.12 (m5 2H), 2.57 (s5 3H)，2.89 (m，3H)，3.20 (m，2H)，3.67 (m，1H)，3.84 (m，1H)，4.04 (m5 2H)， 4.21 (m5 1H)，4_47 (m，1H)，4.98 (m，1H), 5.53 (m，1H)，6.74 (d，1H), 7.31 (s，1H)，8.21 (d，1H) ; MH+ 414· 實例87 3·[[4_(2-甲基-3-丙-2-基喃唾-4_基）,咬-2-基】胺基】四氫p比洛-1_ 羧酸第三-丁酯 將_甲胺基-1-(2-曱基-3·丙-2-基-咪嗅-4-基）丙稀-1-酮 (方法24，WO 03/076436，1.85克，8.36毫莫耳）、3-胺基碳亞 胺醯胺基四氫吡咯小羧酸第三-丁酯（方法2 ; 2.1克，9_1毫莫 耳）及2-甲氧基乙醇（2〇毫升）合併，並於回流下加熱24小時。 使反應混合物冷卻至環境溫度，並蒸發，而產生黃色黏稠 膠質。添加醚（〜1〇〇毫升），並使混合物振盪與音振。藉抽氣 過濾收集固體沉澱物，及在真空下乾燥，而得標題化合物， 為米汽色固體（863宅克，27%)蒸發濾液，並將所形成之膠質 以醚（〜25毫升）處理，藉抽氣過濾收集固體沉澱物，並在真 空下乾燥，獲得另外之標題化合物，為白色固體，使其於 矽膠上（12克藥筒）藉急驟式層析純化，以DCM中之0-10% =0Η溶離。合併含有產物之溶離份，並蒸發，而得另外之 払題化合物，為白色固體（122毫克，3.5%)。應汉（4⑽ 1·4〇 (m, 9HX 1.49 (d5 6H)5 1.91 (m5 1H)5 2.11 (m5 1H)5 2.48 (s, 3H)5 3.19 1H)5 3.45 (m5 IK), 3.55 (m5 1HX 4.32 (m, 1H)5 5.69 (m3 1H)5 6.86 (d5 120858 -99- 200811169 1H)，7.35-7.43 (m，2H)，8.23 (d，1H) ; MH+ 387.3. 實例88 4-(2-甲基-3-丙-2_基-味嗤-4-基）-N-四氫p比洛-3-基-吨咬-2-胺 使3-[[4·(2-甲基-3_丙_2_基-咪唑·4_基）嘴啶-2-基]胺基]四氫p比 咯小羧酸第三-丁酯（實例87; 855毫克，2.21毫莫耳）溶於DCM (10毫升）中，並添加TFA (2.5毫升）。將反應混合物在環境溫 度下攪拌3小時，然後直接傾倒於SCX-2藥筒（20克）上，並 以DCM (100毫升）與MeOH (100毫升）洗滌。使產物以Me〇H中 之2M氨（100毫升）自藥筒溶離。蒸發鹼性溶離份，獲得琥珀 色膠質（〜500毫克），使其於矽膠上藉急驟式層析純化，以2M 氨/MeOH在DCM中之0-15%梯度液溶離。蒸發含有產物之溶 離份，而產生黃色膠質，將其以醚研製/音振，而得灰白色 固體，將其藉真空過濾收集，並乾燥，獲得標題化合物， 為灰白色固體（230 毫克，36%)。NMR (400.132 MHz) 1.49 (d，6H)， 1·66 (m，1H)，2.02 (s，1H)，2.48 (s，3H)，2.74 (m5 2H)，2.94 (m，2H)，4.25 (m，1H)，5.68 (m，1H)，6.80 (d，1H)，7.11 (brs，1H)，7.35 (s，1H)，8.20 (d， 1H) ； MH+ 287.4. 實例89 4-(2-甲基-3-丙-2-基·咪唑_4-基）-N-(l-曱基磺醯基四氫吡咯各 基）嘧啶-2-胺 將觸媒DMAP (5毫克）與DIPEA (0.07毫升，0,42毫莫耳）添加 至4-(2-曱基-3-丙-2-基-η米唾-4-基）·Ν·®氫p比洛_3·基“密咬-2-胺 (實例88 ; 62毫克，0·22毫莫耳）在DCM (2毫升）中之經擾拌 溶液内。然後添加氣化曱烷磺醯（0.025毫升，〇·32毫莫耳）， 120858 -100- 200811169 並將反應混合物於環境溫度下攪拌16小時。接著添加另外 之DCM(20毫升）與水（15毫升），並使混合物振盪，然後傾倒 經過相分離藥筒。使有機溶離劑蒸發至乾涸，獲得淡黃色 膠質，將其與水相合併，及在真空中濃縮。使所獲得之黃 色膠質溶於DCM (15毫升）中，以硫酸鎂處理，過濾，且使 慮液於石夕膠上藉急驟式層析純化，以Me〇H在DCM中 之梯度液溶離。將所得之殘留物以謎研製，獲得固體，將 其過濾，並在真空中乾燥，而得標題化合物，為淡黃色固 體(23 毫克，29%)。NMR (400.132 MHz) 1.55 (d，6H)，2·04 (m，1H)，2.26 (m，1H)，2·54 (s，3H)，2.95 (s，3H)，3·25 (m，1H)，3.49-3.62 (m，3H)，4·46 (m，1H)，5.69 (m，1H)，6.93 (d，1H)，7_41-7_49 (m，2H)，8·31 (d，1H); MH+ 365.3. 實例90 3-[[4_(2·曱基-3·丙-2_基-哺唑-4-基）喊啶-2-基]胺基】四氫吡咯小 績醯胺 於130 C下，將4-(2-甲基-3-丙-2-基-味嗅-4-基）-Ν-四氫外b σ各-3-基^密啶-2-胺（實例88 ; 62毫克，〇_22毫莫耳）與磺醯胺（102毫 克’ 1.06毫莫耳）在ι，4-二氧陸圜（2毫升）中之溶液，藉由微 波照射加熱30分鐘。蒸發反應混合物，並將飽和NaHC03水 溶液（10毫升）添加至殘留物中。以DCM (2 X 10毫升）萃取水 層’然後，將合併之有機物質以鹽水洗滌，以硫酸鎂脫水 乾燥，過濾，及蒸發。於矽膠上藉急驟式層析純化，以0-10% MeOH在DCM中之梯度液溶離，獲得標題化合物，為無色固 體（51 毫克，63%)。NMR (400.132 MHz) 1.50 (d，6H)，1.94 (m5 1H)，2.18 120858 -101 - 200811169 (m，1H)，2.48 (s，3H)，3.04 (m，1Η)，3·19 (m，1Η)，3·33 (m，1H)，3.46 (m， 1H)，4.39 (m，1H)，5·65 (m，1H)，6.75 (s，2H)，6.86 (d，1H)，7.29-7.38 (br m，1H)，7.37 (s，1H)，8·24 (d，1H) ; MH+ 366.2. 實例91 l-[3-[[4_(2_甲基_3_丙_2_基-蜂唑-4_基）峨啶·2_基】胺基】四氫吡咯 -1-基】乙嗣 將醋酸酐（0.060毫升，〇·64毫莫耳）逐滴添加至4_(2_甲基_3_ 丙_2_基·味嗤_4_基）四氫ρ比洛-3H咬-2-胺（實例88 ; 100毫 克，0.35毫莫耳）與tea (0.10毫升，〇_72毫莫耳）在DCM (3毫 升）中之溶液内。將反應混合物攪拌2小時，然後添加水（5 毫升）與DCM (5毫升）。使混合物經過pTFE過濾杯過濾，蒸 發’接著於石夕膠上藉急驟式層析純化，以DCM中之1〇0/〇 MeOH溶離，獲得無色膠質。將膠質以醚研製，過濾，及乾 秌，而得標題化合物，為無色固體（79毫克，69%)。NMR (400.132 MHz)(旋轉異構物）149 細，6H)，188 2 〇3 (m，4H)，2 〇5_ 2·24 (m，1H)，2·48 (m，3H)，3.43 (m，2H)，3·56_3·75 (m，2H)，4·31_4·44 (m， 1H)，5.66 (m，1H)，6.86 (m，1H)，7.34-7.49 (m，2H)，8·24 (m，1H) ; MH+ 329.3. 實例92 N-[l-(3-氣基丙基磺醯基）四氫吡咯_3•基】甲基各丙冬基_ 咪唑-4_基）嘧啶-2-胺 裇題化合物係藉由實例3之程序，並於相同規模下使用 4·(2-甲基-3-丙_2_基-味唑斗基）_N_四氫吡咯_3_基-嘴啶·2_胺（實 例S8)作為起始物質而製成。nmr (4〇〇 I% I.%汍册)，2 % 120858 -102- 200811169 (m5 1H)? 2.18 (m5 2H)5 2.28 1H)5 2.54 (s5 3H)5 3.25-3.45 (m5 4H)5 3,56 (m5 1H)5 3.65 (m5 1H)5 3.79 (t5 2H)5 4.47 (m5 1H)5 5.69 (m, 1H)3 6.93 (d5 1H)，7·42 (s，1H)，7·48 (m，1H)，8% (山邱；€ 實例93-98 下列化合物係藉由墙L A 精田只例68之程序，並於相同規模下使用 4-(2-甲基-3-丙-2-基-畔# 木1 4基）-Ν-四氫ρ比洛-3-基-π密咬-2-胺（實例88)，適當酸起始物&lt; 〇 實例 ------- 化合物 ^η 巧0 NMR (500.133 MHz) m/z 93 4-〇[3七4-(2_ 甲基 4 丙-2-基·咪唑_4·基）遞 °定-2-基]胺基]四氫 叶匕洛-1_基]-2-酮基-乙 基]六氫吡啶-1受酸^ 第三-丁酯 (373K) 1.09 (m，2H)，1.40 (s， 9H)，1.51 (d，6H)，1.67 (m， 2H)，1.87-2-06 (m5 2H)，2· 17 (m，3H)，2·49 (s，3H)，2.74 (m， 2H)，3.28-3.77 (m，4H)，3.88 (m，2H)，4.43 (m，1H)，5.58 (m， 1H)，6.82 (d，1H)，6.94 (m， 1H)? 7.33 (s, 1H)3 8.23 (d? 1H) 512.4 94 4-[3-[3-[[4-(2_ 曱基 丙_2_基-味°坐_4_基）ϋ密 淀-2-基]胺基]四氫 叶匕口各-1-基]-3-_基·內 基]六氫吡畊-1-羧酸 第三-丁酯 (373K) 1.41 (s，9H)，1.50 (d， 6H)，1.89-2.26 (m，2H)， 2.32-2.43 (m，6H)，2.47 (s，3H)， 2.61 (m，2H)，3.25-3.83 (m， 8H)，4.43 (m，1H)，5·58 (m， 1H)，6.81 (d，1H)，6.91 (s，1H)， 7.29 (s，1H)，8.22 (d，1H) 527.3 95 4-[3-[3-[[4-(2•甲基 丙-2-基-味σ坐-4-基 &gt;密 °定-2-基]胺基]四氫 叶匕17各-1-基]_3-酮基-兩 基]六氫吡啶-1-羧酸 第三-丁酯 (373K) 1.01 (m，2H)，1.40 (s， 9H)，1.42-1.54 (m，9H)，1.63 (m，2H)，1.89-2.28 (m，4H)， 2.48 (s，3H)，2.70 (m，2H)， 3.27-3.73 (m，4H)，3.89 (m, 2H)，4.43 (m，1H)，5·58 (m， 1H)，6.81 (d，1H)，6.93 (m， 1H)，7.32 (s，1H)，8.23 (d，1H) 526.4 120858 -103- 200811169 實例 化合物 NMR (500.133 MHz) m/z 96 4-甲基-4-[3-[[4-(2-甲 基-3-丙-2-基米嗤_4_ 基）嘧啶-2-基]胺基] 四氫吡咯小羰基]六 氫吡啶小羧酸第三_ 丁酯 (373K) 1.18 (s，3H)，1·36 (m， 2H)，1·40 (s，9H)，1·51 (d，6H)， 1.94 (m，1Η)，2·06 (m，2Η), 2.15 (m，1H)，2_49 (s，3H)， 3.15(m，2H)，3.44-3.58 (m， 4H)，3.69-3.82 (m，2H)，4.41 (m，1H)，5.57 (m，1H)，6.82 (d， 1H)，6_93 (m，1H)，7·33 (s， 1H)，8.23 (d，1H) 512.6 97 (3R)-3-[2-l&gt;[[4-(2-甲基 -3-丙-2-基-口米唾-4·基） u密唆-2-基]胺基]四 氮p比洛-1-基]-2-嗣基-乙基]六鼠p比°定-1-幾^ 酸第三·丁酯 1.21 (m，1H)，1.32-1.43 (m， )，1.51 (d，6H)，1·57 (m， 1H)，1.78 (m，1H)，1.84-2.29 (m，5H)，2·48 (s，3H)，2.67 (m， 1H)，2.85 (m，1H)，3.27-3.83 (m，6H)，4.43 (m，1H)，5.58 (m， 1H)，6.81 (d，1H)，6.94 (m， 1H)，7.32 (s，1H)，8.23 (d，1H) 512.6 98 (3S)-3-[2-[3-[[4-(2-甲基 -3-丙-2-基-味唾-4-基） 。密口定-2-基]胺基]四 氮比洛基]-2-目同基· 乙基]六氣”比°定-1-竣^ 酸第三-丁酯 (373K) 1.21 (m，1H)，1.33-1.43 (m，10H)，1.51 (d，6H)，1.57 (m，1H)，1.78 (m，1H)， 1.84-2.29 (m，5H)，2.49 (s，3H)， 2.67 (m5 1H)，2.85 (m，1H)， 3.28-3.83 (m5 6H)，4.43 (m， 1H)，5.58 (m，1H)，6.82 (d， 1H)，6.94 (m，1H)，7.33 (s， 1H)，8.23 (d，1H) 512.6 實例99-104 下列化合物係精由實例80之程序，並於相同規模下使用 所指示之起始物質替代4-[2-[4-[[4-(2-甲基-3-丙-2-基-味唆_4_基） 哺π定-2-基]胺基]-1-六氫吨σ定基]-2-S同基-乙基]六氫p比咬_ι_魏酸 第三-丁酯（實例68)而製成。 120858 104- 200811169 實例 化合物 NMR (500.133 MHz) m/z SM 99 H3-[[4-(2-甲基-3-丙·2-基-味。坐-4-基）嘧啶-2-基]胺 基]四氫ρ比洛_1_ 基]-2_(4-六氫外匕 啶基）乙酮 (500.133 MHz) 0.95-1.10 (m, 2H)，1·47 (m，6H)， 1·58 (m，2Η)，1·76 (m， 1Η)，1.87-2.00 (m5 1Η)， 2.04-2.21 (m, 3H)5 2.38-2.48 (m5 5H)5 2.87 (m，2H)，3.34-3.53 (m， 4H), 4.26-4.42 (m，1H)， 5.65 (m，1H)，6.84 (m， 1H)，7.30-7.49 (m，2H)， 8.22 (m? 1H) 412.3 實例93 100 Η3-[[4·(2-甲基-3-丙-2-基_味唾-4-基）唯。定_2_基]胺 基]四氫吡洛小 基]-3-六氫吡畊 -1-基-丙-Ι-g同 1.48 (m，6H)，1.87-2.01 (m，1H)，2.02-2.22 (m， 1H)，2.22-2.40 (m, 6H)， 2.44-2.52 (m, 5H), 2.63 (m，2H)，2.67 (m，2H)， 3.24-3.70 (m，4H)， 4.27-4.43 (m，1H)，5.65 (m，1H)，6.84 (m，1H)， 7.31-7.49 (m, 2H)，8.22 (m，1H) 427.2 實例94 101 1-[3-[[4-(2-甲基-3-丙-2-基米嗤-4-基）嘧啶_2_基]胺 基]四氫吡洛-1-基]-3-(4-六氫外匕 σ定基）丙-1-酮 0.97 (m5 2H)5 1.24-1.33 (m，1H)，1.35-1.61 (m， 10H)，1.87-2.24 (m，4H)， 2·34_2·47 (m，5H)，2.89 (m，2H)，3.22-3.73 (m， 4H)，4.26_4_43 (m，1H)， 5.65 (m，1H)，6.84 (m， 1H)，7.31-7.48 (m，2H)， 8.22 (m，1H) 426.3 實例95 102 (4-甲基冰六氫毗 啶基）-[3-[[4-(2-甲 基-3-丙-2-基-口米 唑-4-基）嘧咬-2-基]胺基]四氫毗 洛-1-基]甲酮 (373K) 1.15 (s5 3H)? 1.35 (m，2H)，1.50 (m，6H)， 1.93 (m，1H)，2.02 (m， 2H)，2.15 (m，1H)，2.47 (s，3H)，2.64-2.78 (m， 4H)，3.46-3.56 (m，2H)， 3.72 (m，1H), 3.80 (m， 1H)，4.39 (m，1H)，5.58 (m，1H)，6.81 (d，1H)， 6.88 (m，1H)，7·29 (s， 1H)，8.22 (d，1H) 412.4 實例96 120858 • 105 - 200811169 實例 化合物 NMR (500.133 MHz) m/z SM 103 1-[3-[[4-(2-甲基-3-丙-2-基-味嗤-4-基）p密咬-2-基]胺 基]四氫吡咯-1-基]-2-[(3S)-3-六氫 吡啶基]乙酮 1.04 (m，1H)，L33 (m， 1H)，1·44_1·55 (m，7H)， 1.66-2.22 (m，7H)，2.40 (m，1H)，2·46 (s，3H)， 2.78-2.94 (m3 2H)5 3.25-3.54 (m，4H)， 4·27-4_43 (m，1H)，5.65 (m，1H)，6.84 (m，1H)， 7.33-7.49 (m，2H)，8.22 (m，1H) 412.4 實例97 104 H3-[[4-(2-甲基冬 丙-2_基-嗓。全-4-基）嘧啶-2-基]胺 基]四氫吡咯-1-基]-2-[(3R)-3-六氫 吡啶基]乙酮 1.04 (m，1H)，1.33 (m， 1H)，1.44-1.55 (m，7H)， 1.66-2.11 (m，7H)，2.39 (m5 1H)，2_46 (s，3H)， 2·77_2·93 (m，2H)， 3.23-3.73 (m5 4H), 4.26-4.43 (m5 1H)5 5.65 (m，1H)，6.84 (m，1H)， 7.32-7.48 (m，2H), 8.22 (m，1H) 412.4 實例98 實例105 4-(2-甲基各丙_2-基_味唑-4-基）_Ν·[1-(3-四氩吡咯-1_基丙基磺醯 基）四氫吡洛-3_基】嘧咬-2_胺 將氯化3-氯基-1-丙基績醯（〇·〇46毫升，〇·38毫莫耳）逐滴添 加至4-(2·甲基-3-丙-2-基-咪唑-4-基）-Ν-四氫吡咯-3-基密啶-2-胺（實例88 ; 73毫克，〇·25毫莫耳）與TEA (0.070毫升，〇·5〇毫 莫耳）在DCM (2毫升）中之溶液内。將反應混合物攪拌3小 時’然後添加水（5毫升）與DCM (5毫升），並攪拌5分鐘。分 離有機層，接著蒸發，獲得灰白色固體，使其溶於ΤΗρ (3 耄升）中，然後添加碘化鈉（5毫克，〇·〇3毫莫耳）與四氫吡咯 (〇·1〇毫升，1.20毫莫耳）。在15(rc下，將反應混合物藉由微 波加熱1小時，接著冷卻，並蒸發。使殘留物藉KPHPLC純 120858 •106- 200811169 化，而得標題化合物，為無色固體（17毫克，15%)。NMR (400.132 MHz，CDC13) 1.56 (d，6H)，1.85 (m，4H)，2.00-2.15 (m，3H)，2.32 (m，1H)，2.58 (s，3H)，2.64-2.78 (m，6H)，3_11 (m，2H)，3.36 (m，1H)，3.55 (m，2H)，3.72 (m，1H)，4.56 (m，1H)，5.58 (m，1H)，5·68_5·93 (m，1H)，6·79 (d，1H)，7.34 (s，1H)，8.19 (d，1H) ; MH+ 462·3· 實例106 4_(2_甲基各丙基味唑冬基）善[l-[3-(4·丙-2-基六氮吡畊_1-基） 丙基績醯基]四氫峨洛-3-基】峨咬-2-胺 將碘化納（5毫克，〇·〇3毫莫耳）與1_異丙基六氫吡畊（116毫 克’ 〇·90毫莫耳）添加至ΝΚ3·氯基丙基磺醯基）四氫吡咯各 基]·4_(2-甲基-3-丙-2-基-咪唑冰基）嘴啶-2-胺（實例92 ; 75毫克， 0.18耄莫耳）在THF (3毫升）中之溶液内。在15〇cc下，將反應 混合物藉由微波加熱45分鐘。使反應混合物冷卻，蒸發， 且使所得之殘留物藉RPHPLC純化，而得標題化合物，為灰 白色固體（49 爱克，52%)。NMR (400·132 mHz，CDC13) 1.33 (d，6H)， 1·59 (t，6H)，2·05 (m，3H)，2·35 (m，1H)，2·61 (t，2H)，2.65 (s，3H)， 2·79-2_97 (m，8H)，3Ό7 (m5 2H)，3.4G (m，2H)，3.56 (m，2H)，3.72 (m，1H)， 4·58 (m，1H)，5·57 (m，1H)，5.78 (m，1H)，6.83 (d，1H)，7.43 (s，1H)，8.25 (d，1H) ; MH+ 519.3. 實例 107-108 下列化合物係藉由實例106之程序，並於相同規模下利用 適當胺製成。 120858 -107- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 107 N-|&gt;[3-(2-甲氧基乙 胺基）丙基磺醯基] 四鼠p比洛-3-基]-4-(2-曱基-3-丙-2-基·味唑 _4_基）嘧啶-2-胺 1·56 (d，6H)，2.08-2.37 (m， 4H)，2.58 (s，3H)，3.03 (m， 4H)，3-11-3.72 (m，8H)，3·37 (s， 3H)，4.54 (m，1H)，5.59 (m， 1H)，6.08 (m，1H)，6.80 (d， 1H)5 7.36 (s5 1H)5 8.19 (d5 1H) 466.3 108 N-j&gt;[3-(4_f 基六氫 ^比呼_1_基）丙基績酿 基]四氫吡咯-3-基]-4-(2-甲基-3-丙-2-基-喃嗤_4_基）哺咬_2_ 胺 1.56 (d，6H)，2.02 (m，3H)， 2·32 (m，1H)，2·39 (s，3H)，2.50 (t，2H)，2.53-2.69 (m, 11H)， 3.07 (m，2H), 3.35 (m，1H)， 3·55 (m，2H), 3·72 (m，1H)， 4.56 (m，1H)，5·58 (m，1H)， 5.72 (m，1H)，6.80 (d，1H)， 7.35 (s，1H)，8.19 (d，1H) 491.3 實例109 N_甲基_3-[[4-(2-甲基_3_丙-2_基_喃唑-4-基）嘴啶-2-基]胺基]四氫 吡咯小羧醯胺 使4-(2-甲基_3_丙-2-基_咪，坐-4-基）-N-四氫p比洛_3_基“密唆-2-胺（實例88 ; 144毫克，〇_5毫莫耳）溶於異氰酸甲酯（1〇5毫克） 在THF (2毫升）中之溶液内，並於環境溫度下攪拌2小時。 添加緩血酸胺樹脂（2〇〇毫克），將反應混合物溫和地攪拌3〇 分鐘，然後過濾，及在真空中蒸發，獲得無色膠質。添加 DCM (0.5毫升）/醚（3毫升），並使溶液於真空中濃縮，而得 標題化合物，為無色泡沫物（51毫克，3〇%pNMR(CDCl3)15i (d，6H)，1.95-2.05 (m，1H)，2.13-2.24 (m，1H)，2.58 (s，3H)，2.74 (s，3H)， 3.37-3.42 (m, 2H)5 3.47-3.61 (m, 2H), 5.47-5.66 (m, 1H)? 6.73 (d3 1H)5 7.43 (s，1H)，8.04 (d，1H). 實例110 N-(2_二甲胺基乙基）各[[4-(2_甲基各丙冬基_咪唑斗基）嘧啶_2_ 120858 -108- 200811169 基]胺基]四氫峨洛-i_叛醯胺 標題化合物係以類似實例22之方式，並於類似規模下利 用4-(2-甲基-3-丙-2-基·口米β全-4-基）-N-凹氫ρ比嘻-3-基-σ密咬-2-胺 (實例88)替代4-(2_甲基-3_丙-2-基-味吐_4_基）_Ν_(4-六氫ρ比。定基） 嘧啶冬胺（實例2)，與適當胺而製成。NMR (CDC13，400 MHz) 1·56 (d，6H)，1.95-2.07 (m，1H)，2.19-2.32 (m，7H)，2.43 (t，2H)，2.57 (s， 3H)，3·28-3·41 (m，3H)，3.43-3.60 (m，2H)，3·66-3·76 (m，1H)，4.49-4.60 (m，1H)，4.89 (s，1H)，5.15 (d，1H)，5.52-5.67 (m，1H)，6_78 (d，1H)，7.32 (s5 1H)，8.21 (d5 1H) ; MH+ 401.6. 實例111 (3S)-3-[[4-(2-曱基_3-丙_2_基·味唑-4·基）响啶-2_基】胺基】六氫吡 啶小羧酸第三-丁酯 將2-氯基-4-(2-曱基-3-丙-2-基』米嗤-4-基）嘴唆（方法5; 5.0克， 21.2毫莫耳）、tea (6·5毫升，46·6毫莫耳）及（3S)-3_胺基六氫 吡啶小羧酸第三-丁酯（4·33克，14.2毫莫耳）添加至DMA (100 宅升）中’並於ll〇°C下加熱16小時。蒸發溶劑，獲得黃色 膠質’添加水（100毫升），並接著以DCM (3 X 150毫升）萃取 混合物。使合併之有機物質脫水乾燥，且在真空中移除溶 劑，而產生深色膠質（7·〇克）。MH+ 4〇1. 實例112 4_(2_甲基_3_丙_2_基·^、唾冰基）具[㈣各六氮被咬基]鳴啶冬胺 使（3S)_3-[[4-(2_甲基_3_丙_2_基·味唑斗基密啶_2基]胺基]六 氬吡疋1-羧酸第二_丁酯（實例^ ; 5·5克，ΐ2·9毫莫耳）溶於 乙如（30笔升）中，並添加丙_2·醇中之6 hC1 (5〇毫升）。將 120858 -109· 200811169 反應物㈣2小時’然後蒸發至乾涸，使所獲得之膠質溶於 水(100毫升)中，並添加固體NaHC〇3,直収應呈鹼性為止。 以DCM (3 X 200毫升）萃取水層，脫水乾燥，及在真空中移 除溶劑，而得黃色膠質。於矽膠上藉急驟式層析純化，以 DCM中之0-10% MeOH溶離，獲得標題化合物，為深色膠質 (2.5 克）。NMR (400.132 MHz，CDCl3) (m, 8H)，1 74 1 82 ㈣ 1H)，1.92-2.00 (m，1H)，2.56 (s，3H)，2.68 (dd，1H)，2.72-2.78 (m，1H)， 2.87-2.92 (m，1H)，3.18-3.22 (m，1H)，3.93-3.96 (m，1H)，5_39 (d，1H)， 5.55-5.67 (m，1H)，6.71 (d，1H)，7.30 (s，1H)，8.19 (d，1H) ; MH+ 301· 實例113 (3R)-3-[[4-(2·甲基-3-丙-2_基-喃唑_4-基）喊啶_2_基]胺基]六氫吡 唆小叛酸第三-丁醋 標題化合物係以類似實例ill之方式，並於類似規模下利 用（3R)-3-胺基六氫吡啶-1-羧酸第三-丁酯作為起始物質而製 成。MH+ 401. 實例114 4-(2-甲基-3-丙-2-基-喃唑冰基）_N-[(3R)_3-六氫吡啶基】喊啶-2-胺 標題化合物係以類似實例112之方式，並於類似規模下利 用（3R)-3_[[4-(2-甲基_3·丙-2-基-咪唑-4-基）嘴啶-2-基]胺基]六氫 吡啶-1-羧酸第三-丁酯（實例113)作為起始物質而製成。NMR (400.132 MHz，CDC13) 1.51-1.57 (m，6H)，L62-1.71 (m，2H)，1.85-2.00 (m，2H)，2.56 (s，3H)，2.81-3.00 (m，3H)，3.24-3.28 (m，1H)，3.34-3.52 (m， 1H)，4.02-4.13 (m5 1H)，5.58-5.65 (m，2H)，6.72 (d，1H)，7.31 (s，1H)，8.19 (d，1H) ; MH+ 301. 120858 -110- 200811169 實例115 4_(2_曱基_3-丙_2_基-咪唑_4_基）-N-[(3S)-l-甲磺醯基_3_六氫吡啶 基]嘧啶-2-胺 將4-(2-甲基-3_丙-2-基-咪唑_4-基）-N-[(3S)-3-六氫吡啶基 &gt;密啶 !胺（實例112 ; 0·30克，〇.1毫莫耳）與ΤΕΑ (0·21毫升，ι·5毫 莫耳）添加至DCM (10毫升）中，然後添加氣化甲烷磺醯（0.091 毫升，1.2毫莫耳）。在攪拌10分鐘後，添加飽和NaHC〇3水 溶液（30毫升），以DCM (3 X 30毫升）萃取混合物，脫水乾燥， 並在真空中移除溶劑，獲得淡黃色膠質。於矽膠上藉急驟 式層析純化，以DCM中之0-5% MeOH溶離，獲得標題化合物， 為白色固體（0.26 克）。NMR (400.132 MHz，CDC13) 1.56-1.59 (m，7H)， 1·69-1·78 (m，1H)，1.89-2.07 (m，2H)，2.57 (s，3H)，2·78 (s，3H)，2.84-2.92 (m，1H)，2.95-3.09 (m，1H), 3.37-3.46 (m，1H)，3.69-3.72 (m，1H)， 4.154.23 (m，1H)，5.25 (d，1H)，5.57 (七重峰，1H)，6.77 (d5 1H)，7.32 (s， 1H)，8.21 (d，1H) ; MH+ 379· 實例116 4-(2-甲基-3-丙-2_基-味唑-4-基）-N-[(3R)-1-甲磺醯基-3·六氩吡啶 基】嘧啶-2_胺 標題化合物係以類似實例115之方式，並於類似規模下利 用4-(2_甲基-3-丙-2-基-味唑基）-N-[(3R)-3-六氫吡啶基]嘧啶-2-胺（實例1H)作為起始物質而製成。NMR (400.132 MHz，CDC13) 1.56-1.66 (m，7H)，1.69-1.78 (m，1H)，1.88-2.00 (m，2H)，2.57 (s，3H)，2.78 (s，3H)，2.83-2.94 (m，1H)，2.95-3.08 (m，1H)，3.37-3.46 (m，1H)，3.69-3.72 (m，1H)，4.15-4.23 (m5 1H)，5.27 (d，1H)，5.56 (七重峰，1H)，6.77 (d， 120858 -Ill - 200811169 1H)，7.32 (s，1Η)5 8·20 (d，1H) ; MH+ 379· 實例117 4_[[5-氣基-4-(2•甲基-3-丙-2-基-味唑冰基）喊啶：基】胺基]六氫 p比咬-1-叛酸第三-丁醋 將2,5_二氣-4-(2-曱基冬丙-2-基-咪唑基）嘴啶（方法6 ; 3 5 克，12·9毫莫耳）、ΤΕΑ(3·95毫升，28·4毫莫耳）及冬胺基六氫 吡啶小羧酸第三-丁酯（2.84克，14.2毫莫耳）添加至DMA (8〇 毫升）中’並於100°C下加熱16小時。使溶劑蒸發至乾酒， 獲得黃色膠質，添加水（100毫升），然後以DCM (3 χ 15〇毫升） 萃取反應物，使合併之有機物質脫水乾燥，並在真空中移 除溶劑，而得標題化合物，為黃色固體（5·5克）。ΜΗ+ 435· 實例118 5-氣基-4-(2-曱基-3-丙-2_基-味唑冰基）·Ν_(4-六氫吡啶基）嘧啶 胺 使4-[[5-氯基-4-(2-甲基-3-丙-2·•基·咪唑斗基）嘧啶·2_基]胺基] 六氫吡啶-1-羧酸第三·丁酯（實例117; 55克，129毫莫耳）溶 於乙腈（30毫升）中，並添加丙_2•醇中之6顧配1(5〇毫升卜 將反應物攪拌2小時，然:後蒸發至乾涸。使所得之殘留物溶 於水（1〇〇 $升）中，並添加固體NaHC〇3，直到反應物呈驗性 (pH 9)為止。接著以DCM (3 χ2〇〇毫升）萃取水層，使合併之 有機物質脫水乾燥，且在真空中移除溶劑，而產生黃色固 體。使其溶於最少量之熱乙腈中，並冷卻，以沉殿固體， 將其過濾。使攄液濃縮’且重複此程序，以獲得另外兩份 批料將其合併，而得標題化合物，為無色固體（丄7克， 120858 -112- 200811169 85%)。NMR (400.132 MHz，CDC13) 1·40 (ddd，2H)，1.53 (d，6H)， 2.00-2.08 (m，2H)，2.58 (s，3H)，2.67-2.73 (m，2H)，3.11 (ddd，2H)， 3.82-3.92 (m，1H)，4.89-5.10 (m，2H)，7.48 (s，1H)，8.26 (s，1H); MH+ 337. 實例119 5-氣基_4_(2-甲基-3-丙_2-基·味唑-4-基）-N-(l_甲基磺醯基-4-六氫 吡啶基）嘧啶-2-胺 標題化合物係以類似實例115之方式，並於類似規模下利 用5-氣基-4-(2-甲基-3-丙-2-基-味峻_4_基）-N-(4-六氮p比唆基密 啶-2-胺（實例118)作為起始物質而製成。NMR (400.132 MHz， CDC13) 1.52 (d，6H)，1.64 (ddd，2H)，2.13-2.17 (m，2H)，2.58 (s，3H)，2·81 (s，3H)，2.85-2.92 (m，2H)，3,75-3.78 (m，2H)，3·87_3·97 (m，1H)，4.90 (七 重峰，1H)，5.12 (d，1H)，7·45 (s，1H)，8.29 (s，1H) ; MH+ 415. 實例120 5·氣基-4-(2-甲基-3·丙_2-基-味嗤_4-基）-N_[l-(2-嗎福淋_4_基乙基 磺醯基）-4-六氫吡啶基】喊啶-2-胺 使5-氣基_4-(2-甲基-3-丙-2-基-咪唑冰基）_N_(4_六氫吡啶基） 嘧啶-2·胺（實例118 ; 0.2克，0.6毫莫耳）與tea (0.12毫升，0.90 毫莫耳）溶於DCM (15毫升）中，並冷卻至-1〇°c。慢慢添加氣 化2-氣乙烷磺醯（0.011克，〇·66毫莫耳），並使反應物溫熱至 環境温度，且攪拌30分鐘，接著添加嗎福啉（〇·2毫升）。在 攪拌16小時後’使反應混合物蒸發至乾涸，然後經由通過 SCX管柱，接著RPHPLC純化，獲得標題化合物，為無色膠 質（146 毫克）。NMR (400.132 MHz，CDCl3) U2 (d，6h)，L57_166 ㈣ 2H)，2.10-2.17 (m，2H)，2.27 (s，6H)，2.58 (s，3H), 2·74-2·77 (m，2H)， 120858 -113- 200811169 2.94-3.01 (m，2H)，3.08-3.12 (m，2H)，3·76-3·79 (m，2H)5 3.89-3.97 (m， 1H)，4·90_4·93 (m，1H)，5.16 (s，1H)，7.46 (s，1H)，8.28 (s，1H) ; MH+ 514. 實例 121-123 下列化合物係藉由實例120之程序，並於相同規模下利用 適當胺製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 121 5-氯-N-[H2-(4-甲基 -1-六氫p比唆基）乙基 石黃醢基]-4-六氫吨咬 基]-4-(2-甲基 _3_ 丙-2-基-咪唑-4-基）嘧啶-2-胺 0.93 (d，3H)，1· 17-1.27 (m， 2Η)，1.32-1.43 (m，1Η)，1.52 (d，6H)，1.56-1.67 (m，4H)， 1.98-2.17 (m，4H)，2.58 (s，3H)， 2.78-2.86 (m，4H)，2.94-3.01 (m，2H)，3.12-3.16 (m，2H)， 3.75-3.78 (m，2H)，3.87-3.96 (m，1H)，4.91 (七重峰，1H)， 5.07 (d，1H)，7.46 (s，1H)，8.28 (s，1H) 526 122 5-氣-N-[l-(2-二甲胺 基乙基-績酿基）-4-六氮？比11定基]-4-(2-甲 基-3-丙-2-基-味吐-4-基）嘧啶_2_胺 1.52 (d，6H)，1.57-1.66 (m， 2H)，2.10-2.17 (m，2H)，2.27 (s， 6H)，2.58 (s，3H)，2.74-2.77 (m， 2H)，2.94-3.01 (m，2H)， 3.08-3.12 (m，2H)，3.76-3.79 (m，2H)，3.89-3.97 (m5 1H)， 4.90-4.93 (m，1H)，5.16 (s，1H)， 7·46 (s，1H)，8.28 (s，1H) 473 123 5_氯基-4-(2-甲基-3-丙-2-基-σ米吐-4-基）-N-[l-(2-四氫叶1： 口各-1-基乙基績酿基）-4-六 氫吡啶基]嘧啶-2-胺 1.52 (d，6H)，1.56-1.65 (m， 2H)，1.79-1.82 (m，4H)， 2.10- 2.13 (m, 2H)，2.53-2.56 (m，4H)，2.58 (s，3H)，2.89-3.00 (m，4H)，3.14-3.17 (m，2H)， 3.76-3.79 (m，2H)，3.88-3.95 (m，1H)，4.89-4.93 (m，1H)， 5.11- 5.12 (m，1H)，7.46 (s，1H)， 8.28 (s，1H) 498 實例124 5-氣-Ν·[1_(3-甲基-3-硝基-丁基）磺醯基-4-六氫吡啶基】-4-(2-甲 120858 -114- 200811169 基_3-丙_2_基-咪唑_4_基）嘧啶_2_胺 使5-氯基-4_(2-甲基-3-丙-2-基-味唑_4-基）_N-(4-六氫吡啶基） 噹啶_2_胺（實例118 ; 0.2克，0·60毫莫耳）與TEA (〇13毫升，〇 9〇 毫莫耳）溶於DCM (7毫升）中。慢慢添加氯化2_氯乙烷磺醯 (〇·〇7耄升，0.66耄莫耳），並使混合物溫熱至環境溫度，且 攪拌30分鐘。使反應混合物蒸發至乾涸，然後溶於DMA (7 毫升）中，接著添加1,8-二氮雙環并[5·4·〇]十一 -7-烯（0.191克， 1.20毫莫耳）與2_石肖基丙烧（0.112克，ι·2〇毫莫耳）。將反應物 於60°C下加熱30分鐘。然後添加水，以DCm (3 X 50毫升）萃 取水層，脫水乾燥，並在真空中移除溶劑。於矽膠上藉急 驟式層析純化，以DCM中之0-5% MeOH溶離，獲得標題化合 物，為黃色膠質。NMR (400.132 MHz，CDC13) 1.52 (d，6H)，1.57-1.66 (m，8H)，2.11-2.15 (m，2H)，2.36-2.41 (m，2H)，2·58 (s，3H)，2.92-2.97 (m， 2H)，2·99_3·03 (m，2H)，3.76-3.79 (m，2H)，3.90-3.99 (m，1H)，4.92 (七重 峰，1H)，5·31-5.37 (m，1H)，7.45 (s，1H)，8·28 (s，1H) ; MH+ 516· 實例125 5_氟-N-[l-(3_曱基_3·确基-丁基）確醯基-4-六氫外b咬基]-4_(2·甲 基-3-丙-2-基-味嗤-4-基）响咬_2-胺 標題化合物係以類似實例124之方式，並於類似規模下利 用5-敦基·4-(2·曱基-3-丙-2-基-味°坐·4-基）-Ν-(4-六氫外b ϋ定基）哺 啶-2-胺（實例137)作為起始物質而製成。NMR (400.132 ΜΗζ， CDC13) 1·55-1·64 (m，14Η)，2.14-2.17 (m，2Η)，2.37-2.41 (m，2Η)，2·60 (S， 3H)，2.92-3.05 (m，4H)，3.77-3.80 (m，2H)，3.85-3.96 (m，1H)，4·92 (d，1H)， 5.49 (七重峰，1H)，7.53 (s，1H)，8·16 (s，1H) ; MH+ 498· 120858 -115- 200811169 實例126 N-[l_(3-胺基-3-甲基·丁基）磺醯基冬六氫吡啶基卜5_氣基冰(2_ 甲基-3_丙-2_基-味嗤-4-基）峨咬-2_胺 使5-氯-N-[l-(3-甲基-3-石肖基-丁基）績醯基冬六氫峨咬 基]-4-(2-甲基_3_丙-2-基-味唑_4_基）嘴啶-2-胺（實例124 ; 189毫 克，0.37毫莫耳）溶於醋酸(20毫升）中，於其中添加鐵（63毫 克’ 1.10¾莫耳）’並將反應物於60 C下加熱1小時。然後.， 使反應物蒸發至乾涸，以LOM NaOH (50毫升）使反應淬滅， 以DCM (3 X 1〇〇毫升）萃取，使合併之有機物質脫水乾燥， 及在真空中移除溶劑，而產生黃色膠質（0.16克，70%)。MH+ 486. 實例127 N-[l-(3-胺基_3_甲基-丁基）磺醯基_4_六氫吡啶基]-5_氟基_4-(2-甲基-3_丙_2_基-味嗤-4-基）癌唆-2-胺 標題化合物係以類似實例126之方式，並於類似規模下利 用5-氟-N-[l-(3•甲基-3-硝基-丁基）磺醯基-4-六氫吡啶基]冰(2-甲基-3-丙-2-基-咪唑-4-基）嘧啶-2-胺（實例125)作為起始物質 而製成。NMR (400.132 MHz，CDC13) 1.16 (s，6H)，1.45 (brs，2H)， 1.55-1.67 (m5 8H)，1·83-1·87 (m，2H)，2.12-2.16 (m，2H)，2.60 (s，3H)， 2.97-3.08 (m，4H)，3.77-3.80 (m，2H)，3.84-3.93 (m，1H)，4.93 (d，1H)，5·49 (七重峰，1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 468. 實例128 5-氣-N-[l_(3-二曱胺基-3-甲基-丁基）磺醯基-4-六氫吡啶 基】-4_(2-甲基-3-丙-2-基-咪唑-4-基）嘧啶-2·胺 120858 -116- 200811169 將MeOH (15毫升）與曱醛（ΐ·〇毫升）添加至N-K3-胺基-3-甲 基-丁基）石黃醯基-4-六氫吡啶基]-5-氯基_4-(2-曱基-3-丙-2-基-喃 嗤-4-基）嘴啶-2-胺（實例126 ; 160毫克，0·33毫莫耳），接著氰 基硼氫化鈉（63毫克，1.0毫莫耳）中，並將反應物攪拌30分 鐘，然後添加NaOH (20毫升）。將反應物以DCM (3 X 50毫升） 萃取，脫水乾燥，並在真空中移除溶劑。於矽膠上藉急驟 式層析純化，以DCM中之(MO% MeOH溶離，獲得標題化合 物，為灰白色泡沫物（0.068 克，44%)。NMR (400.132 MHz，CDC13) 1.04 (s，6H)，1·52 (d，6H)，1·62 (ddd，2H)，1.88-1.92 (m，2H)，2.10-2.14 (m， 2H)，2.21 (s，6H)，2·58 (s，3H)，2.94-3.04 (m，4H)，3.77 (d，2H)，3.88-3.97 (m，1H)，4.91 (七重峰，1H)，5.12-5.19 (m，1H)，7.45 (s，1H)，8.28 (s， 1H) ； MH+ 514. 實例129 N-[l_(3-二甲胺基-3-甲基-丁基）磺醯基-4-六氫吡啶基】·5_氟基 -4-(2-甲基-3-丙-2-基-喃峻-4-基）♦咬_2_胺 標題化合物係以類似實例128之方式，並於類似規模下利 用N-[l-(3-胺基-3-甲基·丁基）石黃蕴基-4-六氮外b唆基]-5-氣基 斗(2-甲基-3-丙_2_基-咪唑·4·基）嘧啶_2_胺（實例127)作為起始 物質而製成。NMR (400.132 MHz，CDC13) 1.03 (s，6Η)，1.55-1.67 (m， 8H)，1.88-1.92 (m，2H)，2.12-2.16 (m，2H)，2·20 (s，6H)，2.60 (s，3H)， 2.96-3.04 (m5 4H)5 3.76-3.79 (m5 2H)5 3.83-3.93 (m? 1H)5 4.99 (d? 1H)? 5.50 (七重峰，1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 496· 實例130 5-氣-N-[l-(3_二甲胺基丙基磺醯基）-4-六氩吡啶基]_4_(2-甲基_3- 120858 -117- 200811169 丙基-咪唑冬基）嘧啶-2•胺 使5-氯基-4_(2_甲基_3_丙-2-基-咪唑_4_基）-N_(4-六氫吡啶基） 嘧。疋胺（實例118; L〇克，2.99毫莫耳）與ΤΕΑ (〇·62毫升，4 5〇 毫莫耳）溶於DCM (30毫升）中，並冷卻至_1〇°c。於其中，慢 忮添加氯化2-氯丙烷磺醯（0.58毫升，3.29毫莫耳），使反應物 μ熱至環境溫度’並攪拌3〇分鐘。然後，使反應混合物蒸 發至乾酒’添加DMA (50毫升），接著為MeOH中之二甲胺溶 液（1耄升）’並將反應物於9〇°c下加熱16小時。然後，使反 應物蒸發至乾涸，且藉RPHPLC純化，而得標題化合物，為 灰白色泡沫物。NMR (400.132 MHz，CDC13) 1.52 (d，6H)，1.56-1.66 (m，2H)，1·93-2_00 (m，2H)，2.07-2.15 (m，2H)，2·22 (s，6H)，2.39 (t，2H)， 2.58 (s，3H)，2·94-3·02 (m，4H)，3.76-3.79 (m，2H)，3.88-3.95 (m，1H)，4.91 (七重峰，1H)，5.30 (s，1H)，7.44 (s，1H)，8.28 (s，1H) ; MH+ 486· 實例 131-134 下列化合物係藉由實例13〇之程序，並於相同規模下利用 適當胺替代二曱胺而製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 131 5-氯基斗(2-甲基-3-丙-2-基-味嗤-4-基）_ N-[l-(3-四氫卩比η各 基丙基績醯基）_4·六 氫外1：σ定基]嘧咬-2-胺 1.52 (d，6H)，1·61 (ddd，2H)， 1 ·76·1.79 (m，4H)，1.96-2.04 (m， 2H)5 2.08-2.15 (m? 2H)5 2.48-2.51 (m，4H)，2.54-2.58 (m，5H)， 2·94_3·05 (m，4H)，3.76-3.79 (m， 2H)5 3.88-3.95 (m，1H)，4.91 (七重峰，1H)，5.23 (s，1H)， 7·45 (s，1H)，8·28 (s，1H) 512 120858 -118- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 132 5-氯基-4-(2-甲基-3-丙-2-基-咪唑_4_基）-N-[l-[3-(l-六氯 P比 σ定 基）丙基磺醯基]-4-六氫^： σ定基]嘴咬-2-胺 1.42-1.46 (m，2H)，1.51-1.66 (m， 10H)，1.93-2.00 (m，2H)， 2.09-2.13 (m，2H)，2.35-2.42 (m， 8H)，2.58 (s，3H)，2.93-3.02 (m， 4H)5 3.76-3.79 (m? 2H)5 3.88-3.97 (m，1H)，4.91 (七重峰， 1H)，5·26 (s，1H)5 7·45 (s，1H)， 8.28 (s，1H) 526 133 5-氣-N-[l-[3-(4-甲基 六氫ρ井-1_基）丙基 磧醯基]-4-六氫ρ比σ定 基]-4-(2-甲基-3-丙-2-基-咪唑冬基）嘧啶-2-胺 1.52 (d，6H)，1.61 (ddd，2H)， 1.94-2.01 (m，2H)，2.10-2.14 (m， 2H)，2.28 (s，3H)，2.41-2.53 (m， 10H)，2.58 (s，3H)，2.93-3.02 (m， 4H)，3.75-3.78 (m，2H)，3.88-3.97 (m，1H)，4.90 (七重峰， 1H)，5.23 (s，1H)，7·44 (s5 1H)， 8.28 (s，1H) 541 134 5·氯i基-4-(2-甲基-3_ 丙-2-基-嗦。坐-4-基）-Ν-〇(3-嗎福啉-4·基 丙基績醯基）冰六氫 吡啶基]嘧啶-2-胺 1.52 (d，6H)，1.61 (ddd，2H)， 1.95-2.02 (m，2H)，2.08-2.16 (m， 2H)，2.42-2.47 (m，6H)，2.58 (s， 3H)，2.93-3.03 (m，4H)，3.70 (m, 4H)，3.76_3.79(m，2H)，3.89-3.96 (m，1H)，4.90 (七重峰， 1H)，5·26 (s，1H)，7.44 (s，1H)， 8.28 (s, 1H) 528 實例135 4_[[5_氣基冬(2-甲基：丙_2_基_啼唑斗基）喊啶：基】胺基】六氫 吡咬-1_羧酸苄酯 將2-氣基-5-氟基-4-(2-曱基-3-丙-2-基j米嗤-4-基）u密咬（方法 8 ; 10克’ 39.4毫莫耳）、DIPEA (15.4毫升，86·7毫莫耳）及4- 胺基六氫吡啶-1-羧酸苄酯（11.0克，47 2毫莫耳）添加至DMA (200毫升）中’並於125ι下加熱2天。使反應混合物蒸發至 乾酒’添加水（1〇〇毫升），並以DCm (3 X 150毫升）萃取反應 物，脫水乾燥，且在真空中移除溶劑，而產生黃色固體。 120858 -119- 200811169 使其溶於DCM中，添加丙-2-醇，然後慢慢地蒸發DCM，而 產生固體。將其過攄，並以醚洗務，使用遽液重複此程序， 獲得另外兩份批料，將其合併，而得標題化合物，為灰白 色固體（13.75 克）。NMR (400.132 MHz，CDC13) 1.38-1.48 (m，2H)，1.55 (d，6H)，2.03-2.06 (m，2H)，2·60 (s，3H)，3·00 (t，2H)，3.85-3.94 (m，1H)， 4.13-4.16 (m，2H)，4.90 (d，1H)，5.14 (s，2H)，5.54 (七重峰，1H)， 7.29-7.37 (m，5H)，7.52 (d，1H)，8·15 (d，1H) ; MH+ 453. 實例136 4- [[5_氟基-4-(2-甲基_3·丙_2_基-味嗤+基）喊咬_2_基】胺基】六氫 吡啶小羧酸第三-丁酯 將2-氣基-5-氟基-4-(2·甲基-3_丙-2-基-味u坐冬基）嘴σ定（方法 8; 5.0克，21.7毫莫耳）、TEA (6.03毫升，43.3毫莫耳）及4-胺 基六氫吡啶-1·羧酸第三_丁酯（4.33克，21.7毫莫耳）添加至 DMA (80毫升）中’並於ii〇°c下加熱2天。使溶劑蒸發至乾 涸’獲得黃色膠質，添加水（100毫升），並以DCM (3 X 150毫 升）萃取水層。使合併之有機物質脫水乾燥，且在真空中移 除溶劑，而得黃色固體（7.2克，87%)。MH+ 419. 實例137 5- 氟基-4-(2_甲基-3·丙-2-基-味唑_4_基）六氫吡啶基）嘧咬 -2-胺 將EtOH (700毫升）中之4-[[5_氟基士(2_甲基-3-丙_2_基』米唑冰 基）¾ °定-2·基]胺基]六虱峨咬-1-叛酸爷g旨（實例I% ; 13.75克， 30.4毫莫耳）與l〇%Pd/C(1.3克），於25°C及5巴壓力之氫下攪 拌18小時。使反應混合物經過矽藻土過濾，並在真空中移 120858 -120- 200811169 除溶劑，而產生黃色固體。使其溶於熱乙腈中，然後冷卻， 以沉澱固體，將其過濾，並乾燥。使用濾液重複此程序， 獲得另外之物質，接著將批料合併，而得標題化合物，為 無色固體（7·5 克）。NMR (400.132 MHz，CDC13) 1.41 (ddd，2H)，1.56 (d，6H)，2.04-2.06 (m，2H)，2.60 (s，3H)，2·71 (t，2H)，3·00-3·15 (m，2H)， 3.78-3.87 (m，1H)，4.95 (d，1H)，5.59-5.62 (m，1H)，7·53 (d，1H)，8.14 (d， 1H) ； MH+ 319. 實例138 5-氟基-4-(2•甲基-3-丙-2-基·味嗤-4_基）-N_(l-甲基續醯基-4-六氫 吡啶基）嘧啶-2-胺 使1-甲磺醯基六氫吡啶冬胺（0.098克，0·55毫莫耳）懸浮於 異丙醇（2毫升）中，然後添加2-氯基-5-氟基-4-(2-曱基-3-丙冬 基_咪唑-4-基 &gt;密啶（方法8 ; 70毫克，0.27毫莫耳）、TEA (0.11 毫升，0·82毫莫耳）、碘化鈉（12毫克，〇_〇8毫莫耳），並在ι6〇 C下’將混合物藉由微波加熱5〇〇分鐘。於真空中移除溶劑， 並在矽膠上藉急驟式層析純化，以0-5% Me〇H/DCM之梯度液 溶離。合併含有產物之溶離份，並蒸發，而得膠質，將其 以醚研製，接著蒸發，而得標題化合物，為乳黃色固體（52 耄克，48%)。NMR (4〇〇 132 MHz，CDCl3) ! 48 (d，6H)，i % (m，2H)， 2·10 (m，2H)，2.53 (s，3H)，2.75 (s，3H)，2.84 (m，2H)，3.70 (m，2H)，3.81 (m，1H)，4.81 (d，1H)，5.41 (m，m)，7.45 (d，1H)，8.G9 (d，1H) ; MH+ 397. 實例139 N [1-(2-一曱胺基乙基確醯基)冬六氫峨咬基]_5_氟基_4_(2_曱基 1丙_2·基-味唑冰基）嘯啶_2胺 120858 -121 - 200811169 使5-氟基-4·(2-甲基-3-丙-2-基-味唑斗基）_N-(4-六氫吡啶基） 嘧啶_2·胺（實例137; 200毫克，〇·62毫莫耳）溶於dcm中，添 加TEA (0.26毫升，1.87毫莫耳），並使反應物冷卻至〇。。。將 氯化2-氯乙烷磺醯（〇.〇8毫升，〇·75毫莫耳）逐滴添加至已冷卻 之溶液中，將反應物授拌20分鐘，然後添加Me〇H中之二甲 胺（1毫升）。在攪拌1小時後，於真空中移除溶劑，並使殘 留物藉RPHPLC純化，而得標題化合物，為膠質（82毫克）。 NMR (400.132 MHz，CDC13) 1.55-1.66 (m，8H)，2.11-2.15 (m，2H)，2.28 (s，6H)，2.60 (s，3H)，2.74-2.78 (m，2H)，2.96-3.02 (m，2H)，3·09-3·12 (m， 2H)，3.76-3.79 (m，2H)，3.84_3_93 (m，1H)，4.99 (d，1H)，5.50 (七重峰， 1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 454. 實例140至142 下列化合物係藉由實例139之程序，並於相同規模下利用 適當胺製成。 實例 化合物 NMR (400.132 MHz, CDC13) 140 5-氟基_4-(2-曱基-3-丙 -2-基_。米唾基） !&gt;0四氫吡咯_1_基乙 基磺醯基&gt;4-六氫吡 11定基]哺咬-2-胺 1.55-1.66 (m，8H)，1.77-1.83 (m，4H)，2.11-2.15 (m，2H)， 2.52-2.58 (m，4H)，2.60 (s，3H)， 2.90-2.94 (m，2H)，2.96-3.02 (m，2H)，3·14·3·18 (m，2H)， 3.76-3.79 (m? 2H)? 3.83-3.92 (m，1H)，4.94 (d，1H)，5.49 (七重峰，1H)，7.52 (d，1H)， 8.15 (d，1H) 120858 -122- 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 141 Ν·[1-[2-(7-氮雙環并 [2.2.1]庚-7-基）乙基石黃 蕴基]-4-六氯Ρ比σ定 基]-5-氟基-4_(2-甲基 -3-丙-2-基-。米唾-4-基） 嘴唆-2-胺 1.35 (d，4H)，1.55-1.66 (m， 8H)，1.70-1 ·77 (m，2H)，1.94 (s， 2H)，2.11-2.17 (m，2H)，2.60 (s， 3H)，2.79-2.83 (m，2H)， 2.96-3.03 (m，2H)，3.11-3.15 (m，2H)，3.26-3.28 (m，2H)， 3.75-3.80 (m，2H)，3.82-3.91 (m，1H)，4.96 (d，1H)，5.49 (七重峰，1H)，7_52 (d，1H)， 8.15 (d，1H) 506 142 Ν-[1·[2-(6-氮雙環并 [2·2·2]辛-6_基）乙基磺 酿基]-4-六氮^比咬 基]-5-象基-4-(2-甲基 -3-丙-2-基-啼σ圭-4-基） 嘧啶-2-胺 1.47-1.66 (m，14H)，1.86-1.95 (m，4H)，2.11-2.16 (m，2H)， 2.60 (s，3H)，2.70-2.73 (m，2H)， 2.92-3.03 (m，4H)，3.09-3.13 (m，2H)，3.76-3.80 (m，2H)， 3.83-3.92 (m，1H)，4.98 (d， 1H)，5.49(七重峰，1H)，7.51 (d，1H)，8.15 (d，1H) 520 實例143 Ν·[1-(3-氣基丙基績酿基)-4-六氮峨咬基】-5_氟基-4-(2-甲基-3-丙 -2_基-咪唑-4_基）嘧啶-2-胺 使5-氟基-4-(2-甲基-3-丙-2-基-咪唑斗基）-N-(4-六氫吡啶基） 嘧啶-2-胺（實例137; 1.0克，3.14毫莫耳）與TEA (0.66毫升，4.71 毫莫耳）溶於DCM (30毫升）中，並冷卻至-10°C。添加氯化2-氯丙烧績醯（0.66毫升，4.71毫莫耳），並使反應物溫熱至環 境溫度，且攪拌30分鐘。使反應物蒸發至乾涸，並於矽膠 上藉急驟式層析純化，以DCM中之0-5% MeOH溶離，而得標 題化合物，為灰白色固體。NMR (400.132 MHz，CDC13) 1.55-1.67 (m，8H)，2.13-2.17 (m，2H)，2.26-2.33 (m，2H)，2.60 (s5 3H)，2.97-3.04 (m5 2H)，3.11 (t，2H)，3.70 (t，2H)，3.78-3.81 (m，2H)，3.85-3.94 (m，1H)，4.95 120858 -123- 200811169 (d，1H)，5·49 (七重峰，1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 459. 實例144 Ν·[1-(3-二甲胺基丙基橫醯基)-4-六氫π比咬基卜氟基曱基 -3-丙-2-基-味嗤-4-基）喊咬-2-胺 將MeOH中之二甲胺（1.0毫升）添加至N-[l_(3-氣基丙基磺醯 基）-4-六鼠咐σ定基]-5-氟基-4-(2-甲基-3_丙-2-基-味唆-4-基户密咬 -2-胺（實例143 ; 0.14克，0.31毫莫耳）在DMA (10毫升）中之溶 液内，並於90°C下加熱16小時。然後，使反應物蒸發至乾 涸，並藉RPHPLC純化，而得標題化合物，為膠質（91毫克）。 NMR (400.132 MHz，CDC13) 1.55-1.67 (m，8H)，1.94-2.01 (m，2H)， 2.11-2.15 (m，2H)，2.22 (s，6H)，2.39 (t，2H)，2.60 (s，3H)，2.95-3.02 (m， 4H)，3.76-3.79 (m，2H)，3.83-3.92 (m, 1H)，5.06 (d，1H)，5.50 (七重峰， 1H)，7.51 (d，1H)，8.15 (d，1H) ; MH+ 468. 實例145至166 下列化合物係藉由實例144之程序，並於相同規模下利用 適當胺製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 145 5_氣基-4-(2-曱基丙 -2-基-味σ坐_4_基）_N-[1-(3_四氫p比洛-1_基丙 基磺醯基&gt;4-六氫吡 啶基]嘧啶-2-胺 1.55-1.66 (m，8H)，1.77-1.80 (m，4H)，1·98_2·〇5 (m，2H)， 2.11-2.15 (m，2H)，2.50-2.53 (m5 4H)，2·56_2·60 (m，5H)， 2.94-3.06 (m，4H)，3.77 (d， 2H)，3.83-3.92 (m，1H)，5.05 (d，1H)，5.50 (七重峰，1H)， 7.51 (d，1H)，8.15 (d，1H) 494 —----- 120858 -124- 200811169 實例 化合物 NMR (4⑽.132 MHz，CDC13) m/z 146 5-敗基-4-(2_甲基-3-丙 -2-基-味 11 坐-4-基）-N-[l-[3-(1-六鼠ρ比σ定基）丙 基石黃醯基]-4-六氫ρ比 σ定基]嘴唆-2-胺 1.41-1.46 (m, 2H)? 1.52-1.66 (m，12H)，1.94-2.01 (m，2H)， 2.11-2.15 (m3 2H)5 2.32-2.42 (m，6H)，2·60 (s，3H)，2.94-3.03 (m，4H)，3.76-3.79 (m，2H)， 3.84-3.92 (m，1H)，5.06 (d， 1H)，5.50(七重峰，1H)，7.51 (d，1H)，8.15 (d，1H) 508 147 5-氟-N-[l-[3-(4-甲基六 氫吡畊-1-基）丙基磺 醯基]-4-六氫ρ比唆基]-4-(2-甲基-3-丙-2-基-口米 唑-4-基）嘧啶_2-胺 1.55-1.67 (m，8H)，1.94-2.02 (m，2H)，2.11-2.15 (m，2H)， 2.29 (s，3H)，2.44-2.56 (m， 10H)? 2.60 (s5 3H)? 2.94-3.03 (m，4H)，3.75-3.78 (m，2H)， 3.84-3.93 (m，1H)，5.09 (d， 1H)，5.49(七重峰，1H)，7.51 (d，1H)，8.15 (d，1H) 523 148 5-氣基-4-(2-甲基_3-丙 -2-基-咪唑-4-基 (3-嗎福淋-4-基丙基石黃 醯基）-4-六氫p比。定基] 嘧啶-2_胺 1.55-1.67 (m，8H)，1.95-2.02 (m，2H)，2.12-2.16 (m，2H)， 2.42-2.47 (m，6H)，2·60 (s，3H)， 2.94-3.04 (m, 4H)5 3.69-3.71 (m，4H)，3.75-3.79 (m，2H)， 3.84-3.93 (m，1H)，5.08 (d， 1H)，5.48 (七重峰，1H)，7.51 (d，1H)，8.15 (d，1H) 510 149 N-[l-[3-(6_l 雙環并 [2·2·2]辛-6_基）丙基石黃 酿基]-4-六氳ρ比唆 基]_5_氟基-4-(2-甲基 -3-丙-2-基·口米峻_4_基） ϋ密咬-2-胺 1.44-1.66 (m，15H)，1.87-1.97 (m，4H)，2.11-2.15 (m，2H)， 2.48-2.51 (m，1H)，2.58-2.61 (m，5H)，2.68 (s，2H)，3.07-2.95 (m，4H)，3.76-3.79 (m，2H)， 3.84-3.93 (m，1H)，4.98 (d， 1H)，5.50 (七重峰，1H)，7.52 (d，1H)，8·15 (d，1H) 534 120858 125- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 150 N-[l-[3-(7-氮雙環并 [2.2.1]庚-7-基）丙基磺 醯基]-4·六氫p比唆 基]-5-敗基-4-(2-甲基 -3-丙-2-基米α坐-4-基） ϋ密σ定-2-胺 1.28-1.29 (m，5H), 1.55-1.71 (m，11H)，1·92_1·99 (m，2H)， 2.11-2.15 (m5 2H)，2·45 (t，2H)， 2.60 (s，3H)，2.95-3.02 (m，2H)， 3.06-3.10 (m，2H)，3.23-3.25 (m，2H)，3.76-3.80 (m，2H)， 3.84-3.93 (m，1H)，5.03 (d， 1H)，5.50 f 七重峰，1H)，7.52 (d，1H)，8·15 (d，1H) 520 151 N-[l-[3-(環丙胺基）丙 基磺醯基]-4-六氫吡 ϋ定基]-5-氟基-4-(2-甲 基-3-丙-2-基-味^坐-4- 基）嘧啶-2-胺 (DMSO) 0.18-0.22 (m? 2H)? 0.34-0.38 (m，2H)，1.49-1.51 (m，7H)，1.52-1.59 (m，2H)， 1.76-1.83 (m，2H)，1·95 (d， 2H)，2.01-2.05 (m，1H)，2.49 (s， 3H)，2.66 (t，2H)，2.88 (t，3H)， 3.04-3.08 (m，2H)，3.62 (s，2H)， 3.78 (t，1H)，5.43 (s，1H)，7.22 (s，1H)，7.32 (d，1H)，8.37 (d， 1H) 480 152 N-[l-[3-(環戊基胺基） 丙基磺醯基]-4-六氫 外匕σ定基]-5-亂基-4-(2-甲基-3-丙-2-基米ϋ坐 -4-基）嘧啶-2_胺 508 153 Ν_[1-[3-(環丁基胺基） 丙基績醯基]-4-六氫 p比咬基]-5-氣基-4-(2-甲基_3_丙-2-基米峻 -4-基）嘧啶_2-胺 (DMSO) 1.49-1.51 (m，6H)， 1-52-1.83 (m，9H)，1.96 (d, 2H)，2.06-2.12 (m，2H)，2·50 (s， 3H)，2.90 (d，2H)，3.05-3.09 (m，2H)，3.12 (t，1H)，3·18_3·19 (m，1H)，3·61 (d，2H)，3.79 (t， 1H)，5.43 (s，1H)，7·23 (s5 1H)， 7·32 (d，1H)，8.36-8.37 (m，1H) 494 154 5_說基-4-(2-曱基·3-丙 -2_基-味吐-4-基）-N-[l-[3-^ _2_基胺 基）丙基磺醯基]-4·六 氫吡啶基]嘧啶-2-胺 482 120858 -126- 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 155 5-氟 _Ν-[1-[3-(甲基-丙 -2-基-胺基）丙基磺醯 基]-4-六鼠说σ定基]-4-(2-甲基-3-丙-2-基-咪 唾-4-基）嘴唆-2-胺 496 156 3-[3-[[4-[[5·氟基-4-(2-甲 基-3-丙-2-基-味。全-4-基）η密ϋ定-2-基]胺基]-ΙΑ 氮 ？比 17定基]績 酿基] 丙基-甲基-胺基]丙腈 507 157 N-[l-[3-(一 氮四園-1-基）丙基續酸基]-4-六 氫吡啶基]-5-氟基 -4-(2_甲基-3-丙-2-基-咪唾-4-基）痛咬-2-胺 480 158 Ν-[1·[3-(乙基-甲基-胺 基）丙基磺醯基]-4-六 氫吡咬基]-5-氟基 -4-(2-曱基-3-丙-2-基-口米唾-4-基）續。定-2_胺 482 159 N-[l-(3-二乙胺基丙基 石黃酿基）-4-六氮^比唆 基]-5-氟基-4-(2-甲基 -3-丙-2-基-味ϋ坐-4-基） 嘧啶-2-胺 496 160 N-[l-[3-(環丙基-甲基 胺基）丙基績酿基]_4_ 六氫^比σ定基]-5-氟基 -4-(2-甲基-3-丙-2-基-咪唑-4-基）嘧啶-2-胺 494 120858 127- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 161 5-氟-N-[l-[3-(2-曱氧基 乙基-甲基-胺基）丙基 石黃酿基]-4-六鼠批°定 基]-4_(2-甲基-3-丙-2-基-味ϋ坐-4-基密唆-2-胺 512 162 3-[乙基-[3-[[4-[[5-氟基 -4-(2-甲基-3-丙-2_基-咪唑-4-基）嘧啶-2-基] 胺基]-1-六氮？比σ定基] 磺酸基]丙基]胺基] 丙腈 521 163 Ν-[1-[3-(Ν-環戊基-Ν-甲 基-胺基）丙基磺醯 基]-4-六氮ρ比σ定基]-5-象基-4-(2-甲基-3-丙-2-基-咪唑斗基）嘧啶-2-胺 522 164 N-[1-|&gt;(N-環丙基-N_ 甲基-胺基）丙基磺醯 基]-4-六鼠此σ定基]-5-氣基-4-(2-甲基-3-丙-2-基-味峻-4-基）嘴咬-2-胺 494 165 Ν-[1-[3-(Ν-環丁基-N-甲基-胺基）丙基磺醯 基]-4-六氫吡啶基]-5-氣基-4-(2_甲基-3-丙-2-基-味n坐—4-基）嘴唆_ 2-胺 508 120858 128- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 166 Ν-[1-[3-(Ν-環丙基甲基 -Ν-甲基-胺基）丙基石黃 酿基]-4-六氫峨唆基]-5-氟基-4-(2-甲基-3-丙 -2-基米。坐-4-基密唆 -2-胺 508 實例167 4_[[5_氟基_4_(2_甲基_3_丙基-味唑_4_基）喊啶_2_基】胺基】_N_(2_ 四氫峨洛-1_基乙基）六氫卩比咬_1·績醯胺 將5-氟基-4-(2-甲基-3-丙-2-基-咪唑-4-基）-Ν-(4-六氫吡啶基） 嘧啶-2-胺（實例137)與TEA (0.044毫升，0.31毫莫耳）在DCM (3 宅升）中之溶液冷卻至-78°C，並逐滴添加二氯化硫醯（0.026 毫升，0_31毫莫耳）。將混合物於j78〇c下攪拌15分鐘，然後， 使其溫熱至環境溫度，並添加ΤΕΑ (0·〇44毫升，0.31毫莫耳） 與1-(2-胺基乙基）四氫吡咯(44毫克，〇·38毫莫耳）。在攪拌6〇 小時後’添加DCM (7毫升），且將反應混合物以水毫升） 洗滌。將水層以另外之DCM (5毫升）洗滌，並使合併之有機 物質通過相分離薄膜，及在真空中蒸發。使殘留物藉 RPHPLC純化，而得標題化合物，為膠質（5〇毫克，33%)。nmr (CDC135 400.132 MHz) 1.52-1.65 (m5 9H)5 1.74-1.81 (m? 4H)? 2.08-2.17 (m，2H)，2·47-2·56 (m，4H)，2.60 (s，3H)，2.64 (t，2H)，2.95 (t，2H)，3.12 (t， 2H)，3.70 (d，2H)，3.80-3.92 (m，1H)，4·89 (d，1H)，5.46-5.59 (m，1H)，7.53 (d，1H), 8·15 (d，1H) ; MH+ 495. 實例168至182 下列化合物係藉由實例167之程序，並於相同規模下利用 120858 -129- 200811169 成。 實例 化合物 NMR (400.132 MHz，CDCI3) m/z 168 N_(2-二乙胺基乙 基）_4_[[5-氟基-4-(2•甲 基-3-丙-2-基米嗤-4-基)^啶-2-基]胺基] 六氫吨咬-1-續醯胺 1.02 (t，6H)，1.50-1.68 (m， 10H)，2.13 (d，2H)，2.53 (q， 4H)，2.57-2.62 (m，4H)，2_94 (t， 2H)，3.06 (t，2H)，3.70 (d，2H)， 3.80-3.91 (m，1H)，4.90 (d， 1H)，5.46-5.59 (m，1H)，7.52 (d，1H)，8.15 (d，1H) 497 169 4_[[5-氟基-4-(2-甲基 -3-丙-2-基-味唾冰基） 嘧啶冬基]胺基]-N-(2-嗎福啉_4_基乙基） 六氫吡啶小績醯胺 511 170 4-[[5-氣基-4-(2-甲基 -3-丙-2-基·^米唾-4-基） 嘧啶-2-基]胺基]-N-[2-(4-甲基六氫口比p井 -1_基）乙基]六氫P比 啶_1_磺醯胺 524 171 4-[[5-氟基-4-(2-曱基 -3-丙-2-基-口米°坐-4-基） 嘧啶-2-基]胺基]-N-(3-四氫吡咯-1-基丙 基）六鼠”比0定-1~ 磺醯胺 509 172 N-(3-二甲胺基 _2,2-二 甲基-丙基）-4-[[5·氟 基-4-(2·甲基-3-丙-2-基-u米a坐_4_基）。密π定_2_ 基]胺基]六氫咐1咬 -1-石黃酿胺 511 120858 -130- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 173 4-[[5-氟基-4-(2-曱基 -3-丙-2-基-。米°坐-4-基） 嘧啶-2-基]胺基]-N-[3-〇六氫峨咬基）丙 基]六氫批淀-1-磺醯胺 1.37-1.64 (m，14H)，1_71 (t， 2H)，3·11 (d，2H)，2.31-2.53 (m，6Η)，2.60 (s，3Η)，2·92 (t， 2H)，3·17 (t，2H)，3·68 (d，2H)， 3.80-3.91 (m，1H)，4.88 (d， 1H)，5.48-5.60 (m，1H)，7.53 (d，1H)，8.15 (d，1H) 523 174 4-[[5-氟基-4-(2-甲基 -3-丙-2-基-口米嗤_4_基） 嘧啶-2-基]胺基]-N-[3-[(3S)-3-氟基四氫 吡咯-1-基]丙基]六 鼠叶b 17定-1-^黃酿胺 527 175 N-(3-二甲胺基-丙 基Μ-[[5·氟基-4·(2-甲 基-3·丙-2-基-0米嗤-4-基）嘧啶-2-基]胺 基]甲基-六氫ρ比 啶-1-磺醯胺 497 176 4-[[5_氟基-4-(2-甲基 -3-丙_2_基-嗦唾-4-基） 嘧啶-2-基]胺基]-N-[2-(1•甲基四氫p比略 -2-基）乙基]六氫峨 啶-1-磧醯胺 509 177 4-[[5-氟基-4-(2-甲基 -3·丙-2-基-味^坐-4-基） 嘧啶-2-基]胺基]-N-(1-甲基-4-六氫p比咬 基）六氫说σ定-1-磺醯胺 495 120858 -131 - 200811169 實例 化合物 NMR (400.132 MHz，CDC13) m/z 178 4-[[5-敗基冰(2-甲基 -3-丙-2-基-σ米唾-4-基） 嘧啶-2-基]胺基]-Ν_ (1-丙-2_基-4-六氫外匕 σ定基）六氫ρ比咬-1-石黃 醯胺 523 179 N-[l-[(3R)-3-二甲胺 基四氫吡咯-1-基]磺 醯基-4-六氫p比咬 基]-5- 基-4-(2-甲基 -3-丙-2-基-哺σ坐-4-基） 嘧啶-2-胺 1.48-1.61 (m，7H)，1.77-1.90 (m，1H)，2.07-2.17 (m，3H)， 2.26 (s，6H)，2·60 (s，3H)， 2.37-2.84 (m，1H)，2.97 (t，2H)， 3.09 (t，1H)，3.34 (appq，2H)， 3·46 (表觀，1H)，3_56 (表 觀，1H)，3·64-3·74 (m，2H)， 3·80-3·92 (m，1H)，4·89 (d， 1H)，5.46-5.58 (m，1H)，7.53 (d，1H)，8.15 (d，1H) 495 180 5-氟-N-[l-[(4-甲基 -1，4_二氮七圜烧-1-基）石頁酿基]-4-六鼠 吡啶基]-4-(2-曱基-3-丙-2-基-η米。坐-4-基）哺 啶-2-胺 495 181 5-氟-N-[l-(4_曱基六 鼠外b P井-1-基）續S龜基 -4-六氮p比唆基]-4-(2_ 甲基-3-丙_2_基-11 米峻 冬基）嘧啶-2-胺 1.54-1.63 (m，7H)，2.10 (m, 3H)，2.32 (s，3H)，2.46 (t, 4H)， 2.60 (s，3H)，2.98 (t，2H)，3.28 (t? 4H)5 3.71 (d5 2H)? 3.80-3.92 (m，1H)，4.87 (d，1H)， 4.46-5.57 (m，1H)，7.53 (d， 1H)，8.15 (d，1H) 481 182 N-(2_二甲胺基-乙 基）冰[[5-1基-4-(2-甲 基-3-丙-2-基米。坐-4-基）嘧啶-2-基]胺基] 六氫吡啶-1-磺醯胺 469 實例183 3-[[4-[[5-氣基-4-(2甲基-3-丙-2-基-哺嗤-4-基）,咬_2_基】胺基】·1- 120858 -132- 200811169 六氫吡咬基]績醯基曱基]六氫吡啶-1-羧酸爷g旨 使5-氟基-4-(2-甲基-3-丙-2-基-咪唑-4-基）-N-(4-六氫吡啶基） 嘧啶-2-胺（實例137; 0.5克，1.57毫莫耳）與TEA (0.33毫升，2.35 毫莫耳）溶於DCM (50毫升）中，然後添加3_(氯基磺醯基曱基） 六氫峨°定-1-魏酸节酯（在W099/45006中之製備62; 0.82克，2.35 毫莫耳）。將反應物撥摔1小時’接著蒸發至乾涸，並通過 SCX管柱。然後，使所獲得之物質於矽膠上藉急驟式層析 純化，以DCM中之0-5% MeOH溶離，而得標題化合物，為黃 色泡沫物（0.4 克，41%)。MH+ 614. 實例184 4-[[4-[[5_氟基-4-(2-甲基_3_丙_2_基-味嗤-4_基），咬-2-基】胺基]-1_ 六氫吡啶基]磺醯基]六氫吡啶_1_羧酸苄酯 於環境溫度下，將DCM(3毫升）中之4-氯基磺醯基六氫吡 啶_1_羧酸苄酯（334毫克）逐滴添加至5-氟基冰(2·甲基-3-丙-2_ 基-咪嗤-4-基）-Ν·(4-六氫ρ比咬基）嘴唆-2-胺（實例137 ; 318毫克） 與TEA (202毫克）在無水DCM (9毫升）中之經攪拌溶液内。2 小時後，將混合物以飽和NaHC〇3水溶液稀釋，並以DCM萃 取。使萃液脫水乾燥，濃縮，並於矽膠上藉急驟式層析純 化，以0-10% MeOH在DCM中之梯度液溶離，而得標題化合 物，為固態泡沫物（570 毫克，95%)。NMR (400.13 MHz，CDC13) 1·50·1·80 (m5 10H)，2.10 (m，4H)，2.60 (s，3H)，2·80 (m，2H)，3·05 (m，3H)， 3.79 (m，2H)，3.90 (m，1H)，4.35 (m，2H)，4.90 (d，1H)，5.13 (s，2H), 5.50 (m，1H)，7.37 (m，5H), 7.52 (d，1H)，8.15 (d，1H) ; MH+ 600. 實例185 120858 -133 - 200811169 5_氟基冬(2_甲基_3_丙-2_基-咪唑_4_基）_]^_[1-(4_六氫吡啶基磺醯 基）-4-六氫吡啶基】嘧啶-2-胺 將MeOH (16宅升）中之4-[[4-[[5-氟基-4-(2-甲基-3·丙-2-基』米 唑斗基）嘧啶_2_基]胺基]小六氫吡啶基]確醯基]六氫吡啶小羧 酸爷醋（實例184 ; 480毫克），使用H_CUBE系統（Thales Nanotechnology)，以10% Pd/C藥筒，在5(rc下，使用全流量氫 (1巴，1毫升/分鐘）氫化。蒸發溶劑，獲得產物，為膠質（344 t 克，92%)。NMR (400.13 MHz，CDC13 )1.5(M.75(m，10H), 2.08 (m， 4H)，2.60 (m，5H)，3·08 (m，3H)，3·22 (m，2H)，3.82 (m，2H)，3·91 (m，1H)， 4·92 (d，1H)，5·50 (m，1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 466· 實例186 5_氟_N_[1-[(1-甲基-4-六氫吡啶基）績醯基]冰六氫吡啶基】_4_(2-甲基-3_丙·2-基_味峻-4-基）,咬-2-胺 於環境溫度下，將5-氟基+(2-曱基-3-丙-2-基-味唑-4-基）-N-[l-(4-六氫吡啶基磺醯基）六氫吡啶基]嘴啶_2_胺（實 例185; 70毫克）與甲醛（37%水溶液，60毫克）在MeOH (1毫升） 中一起攪拌。添加氰基硼氫化鈉（在THF中之1M溶液，0.3 毫升）’並攪拌1小時，然後蒸發溶劑。將殘留物以2M NaOH 稀釋’並以DCM萃取。將合併之萃液以鹽水洗滌，及在真 空中濃縮。藉RPHPLC純化，獲得標題化合物，為無色油（54 毫克，75%)。NMR (400.13 MHz，CDC13) 1.55 (m，8H)，1.80-2.00 (m， 4H)，2.10 (m，4H)，2.28 (s，3H)，2·60 (s，3H)，2·9〇 (m，1H)，2·97 (m，2H)， 3.08 (m，2H)，3.81 (m5 2H)，3.90 (m，1H)，4_88 (d，1H)，5·50 (m，1H)，7.52 (d5 1H)? 8.15 (d? 1H) ； MH+ 480. 120858 -134· 200811169 實例187 5_氟基·4_(2-曱基-3-丙-2-基_味唑-4-基）善[1-[(1-丙_2_基-4·六氫吡 啶基）續醯基】-4-六氫吡啶基】嘧啶胺 於環境溫度下，將5-氟基-4-(2-甲基-3-丙-2-基-味唑冰 基）-N-[l-(4-六氫p比α定基確醯基）冬六氫峨σ定基]。密唆1胺（實 例185 ; 70耄克）與丙酮（35毫克）在MeOH (1毫升）中一起擾 拌。添加氰基硼氫化鈉（在THF中之1M溶液，〇.3毫升），並 攪拌16小時。逐滴添加濃HC1 (在MeOH中稀釋），以調整pH 至6，然後添加另外之丙酮（2〇〇毫克）與氰基硼氫化鈉（在 THF中之1M溶液，0.3毫升），並將混合物攪拌3小時。接著， 將殘留物以2M NaOH稀釋，且以DCM萃取。將合併之萃液 以鹽水洗滌，及在真空中濃縮，然後藉RPHPLC純化，而得 標題化合物，為無色油（54毫克，71%)。NMR (400.13 MHz， CDC13) 1·03 (d，6H)，1.55 (m，8H)，1.80 (m，2H)，2.10 (m，6H)，2.60 (s， 3H)，2.74 (m，1H)，2.87 (m5 1H)，2.98 (m5 2H)，3.07 (m，1H)，3.80 (m，2H)， 3.90 (m，1H)，4.90 (m，1H)，5·50 (s，1H)，7.52 (d，1H)，8.15 (d，1H) ; MH+ 508. 實例188 6-【[5-氟基-4·(2-甲基_3-丙_2_基_哺峻_4-基）,咬-2_基]胺基]_(1 a，5 a，6 a)各氮雙環并[3丄0】己烷-3_羧酸苄酯 將2-氣基-5-氣基-4-(2-甲基-3-丙-2-基-味。坐-4-基）癌σ定（方法 8; 1.53克）攪拌，並在125°C下，與（la，5a，6a)-6-胺基-3-氮雙 環并[3.1.0]己烷-3-羧酸芊酯（在W097/19942中之製備2; 1.54克） 及DIPEA (0.93克）在DMA (12毫升）中一起加熱10小時。使混 120858 -135- 200811169 合物藉蒸發濃縮，然後以2M碳酸納水溶液稀釋，並以DCM 萃取。使萃液於矽膠上藉急驟式層析純化，以〇_1〇〇%Et〇Ac 在DCM中之梯度液溶離’而得標題化合物，為膠質（8⑻毫 克，22%)。NMR 1.42 (d，6H)，1.77 (m，2H)，2.49 (s，3H)，3.46 (m，2H)， 3.61 (m, 2H)，5.06 (m，2H)，5.50 (m，1H)，7.40 (m，7H)，8.36 (d，1H); MH+ 451. 實例189 N-[5-氟基-4-(2·曱基_3_丙-2-基-咪唑_4_基）嘧啶·2_基】-(1 α，5 α， 6 α )_3_氮雙環并[3·1·0]己烷-6_胺 使EtOH (36毫升）中之6-[[5_氟基冰(2·甲基各丙1基-味唑冰 基）嘴啶-2-基]胺基；ΚΙ α，5 a，6 a )-3-氮雙環并[3丄0]己烷-3_羧酸 苄酯（實例18L 72〇毫克），於l〇%Pd/c(3〇〇毫克）存在下，在 1大氣壓及40 C下氫化2小時。使觸媒經過石夕藻土過濾，並 蒸發濾液，而得標題化合物，為膠質（5〇〇毫克，98%)。 (400.13 MHz5 CDC13+ D20) 1.60 (m, 8H), 2.60 (m, 4H), 2.95 (d5 2H)? 3.15 (d? 2H)5 5.56 (m, 1H)? 7.52 (d5 1H)? 8.16 (d5 1H) ； MH+ 317. 實例190 Ν·[5-氟基·4_(2-甲基-3_丙-2-基·味唑_4_基）嘧啶I基】各甲基磺 醯基-(1 a，5 a;，6 a )-3_氮雙環并[3丄〇】已烷各胺 使N-[5_氟基斗(2-甲基-3-丙冬基-味唑斗基）嘧啶冬基]_(1 α， 5α，6α)-3-氮雙環并[3丄0]己烷_6•胺（實例189;仍毫克，〇2ι毫 莫耳）溶於DCM(2毫升）中。添加氯化甲烷磺醯（〇〇25毫升， 〇.32毫莫耳），然後為TEA (〇.〇6毫升，〇 42毫莫耳），並將混 合物於環境溫度下擾拌16小時。蒸發溶劑，並使殘留物於 120858 -136- 200811169 石夕膠上藉急驟式層析純化，以5% MeOH/DCM溶離，而得標 題化合物，為膠質（33 毫克，40%)。NMR (400.132 MHz) 1.56 (d， 6H)，1.87 (s，2H)，2·56 (s，3H)，2.81 (s，1H)，2.96 (s，3H)，3·46 (m，4H)， 5·6〇 (m，1H)，7.40 (s，1H)，7·45 (s，1H)，8.43 (s，1H) ; MH+ 395. 實例191至193 下述實例係以類似實例139之方式，並於類似規模下利用 N [5鼠基-4-(2•甲基-3-丙-2-基-味°坐-4-基密咬-2-基]-(1 α，5 (2， 雙環并『3丄〇1己烷-6-胺（實例189)與適當胺製成。 實例 化合物 π 甶 衣肌 NMR (400.132 MHz, CDC13) m/z 191 氣基-4-(2-曱基 -3-丙-2-基-味σ坐-4-基） 口&amp;、°定-2-基]-3-(2-四歲 吡咯-1-基乙基磺醯 基）-(1 α，5 α，6α)-3-氮 雙環并[3.1.0]己烷-6-胺 1.56 (d，6H)，1.78 (m，6H)，2·53 (m，4H)，2·59 (s，3H)，2.82 (d， 1H)，2·91 (t，3H)，3.18 (t，2H)， 3.48 (m，2H)，3.73 (d，2H), 5.07 (d，1H)，5.55 (m5 1H)，7.54 (d， 1H)，8·17 (d，1H) 478 192 3-(2-二曱胺基乙基 磺醯基&gt;N_[5-氟基 -4-(2-甲基-3-丙-2-基-味σ坐·4_基）σ密唆-2-基]-(1(2,5〇:，6(3：)-3-氮 雙環并[3.1.0]己烷-6-胺 1.56 (d，6H)，1.77 (s，2H)，2.26 (s，6H)，2.59 (s，3H)，2.76 (m, 2H)，2·83 (d，1H)，3.13 (m，2H)， 3.46 (m，2H)，3.73 (d，2H)，5.09 (d，1H)，5.55 (m，1H)，7.54 (d， 1H)，8.17 (d，1H) 452 193 3-[2-(7-氮雙環并 [2.2.1]庚-7-基）乙基磺 醯基]-Ν-[5-氟基-4-(2-甲基-3-丙-2-基-咪唑 -4-基密唆-2-基]-(1 α，5α，6α)-3-氮雙環 并[3.1.0]己烷-6_胺 1.32 (m，4H)，1·56 (d，6H)，1.72 (m，6H)，2·59 (s，3H)，2.79 (m， 2H)，2.84 (d，1H)，3.14 (m，2H)， 3.25 (m，2H)，3.49 (m，2H)，3.72 (d，2H)，5.08 (d，1H)，5·55 (m， 1H)，7.54 (d，2H)，8.17 (d，2H) 504 120858 -137- 200811169 實例194 N-[5-氟基_4-(2-甲基各丙-2-基-咪唑-4-基）嘧啶_2_基】-3-(3-四氫吡 洛-1-基丙基磺醯基）_(1 α，5 α，6 α )_3_氮雙環并[3.1.0】己烷-6_胺 使Ν-[5-氣基-4-(2-甲基-3-丙-2-基-味α坐-4-基）u密σ定-2-基]-(1 〇；， 5 α，6 a )-3-氮雙環并[3·1·〇]己烧-6-胺（實例189 ; 285毫克）與 DIPEA (349毫克）溶於DCM (15毫升）中，並冷卻至_1〇。〇。然 後逐滴添加DCM (2毫升）中之氯化3-氯丙烷磺醯（176毫克）。 使反應混合物溫熱至環境溫度，並攪拌30分鐘，接著蒸發 至乾涸。使殘留物溶於DMF (6毫升）中，並分離成6x1毫升 液份。將DIPEA (39毫克）與四氫吡咯（300毫克）添加至一液份 中，並將反應混合物在70°C下加熱16小時。濃縮反應混合 物，然後藉RPHPLC純化，而得標題化合物，為膠質（56毫克， 73%)。NMR (400.13 MHz，CDC13) 1.57 (d，6H)，1·80 (m，6H)，2.00 (m， 2H)，2.55 (m，9H)，2·83 (d，1H)，3.05 (m，2H)，3.46 (m，2H)，3.72 (d，2H)， 5.08 (d，1H)，5.57 (m，1H)，7.54 (d，1H)，8.17 (d，1H) ; MH+ 492. 實例195至199 下列化合物係藉由實例194之程序，並於相同規模下利用 其餘液份與適當胺製成。 實例 化合物 NMR (400.132 MHz, CDC13) m/z 195 N-[5-氟基-4-(2_甲基 -3-丙-2-基-11 米嗤-4-基） 喷唆-2·基]-3-[3-(l-六 氫外1:咬基）丙基續醯 基]-(1 〇：，5〇：，6〇:)-3-氮 雙環并[3·1·0]己烷-6-胺 1.43 (m，2H)，1.55 (m，10H)， 1.78 (m，2H)，1.97 (m，2H)， 2.36 (m，6H)，2.59 (s，3H)，2.83 (d，1H)，3.02 (m，2H)，3.47 (m， 2H)，3.72 (d，2H)，5·09 (d，1H)， 5.57 (m，1H)，7.54 (d，1H)， 8·17 (d，1H) 506 120858 -138 - 200811169 196 3-[3-(N-環戊基-N-甲 基-胺基）丙基續酿 基]-Ν-[5-氟基-4-(2-甲 基-3-丙-2-基-味β坐-4-基）嘴啶-2-基]-(1 α， 5α，6α)-3_氮雙環并 [3·1·0]己烷-6-胺# 520 197 3-[3-(2,5-二甲基四氫 口比洛-1-基）丙基續酿 基]-Ν-[5-氟基-4_(2-甲 基_3_丙-2-基-味。坐-4-基）嘧啶-2-基]-(1α， 5α，6α)-3_氮雙環并 [3.1.0]己烧-6_胺 # 520 198 3-(3-二甲胺基丙基 磺醯基）-N-[5-氟基 -4-(2-甲基-3-丙-2-基-咪嗤-4-基 &gt;密咬-2-基]-(1«，5〇:，6〇;)-3-氮 雙環并[3.1.0]己烷-6-胺* 1.58 (d，6Η)，1.77 (s，2Η)，1.96 (m，2H)，2.21 (s，6H)，2.37 (t， 2H)，2.59 (s，3H)，2·83 (d，1H)， 3.02 (m，2H)，3·48 (m，2H)， 3.73 (m，2H)，5.08 (d，1H)， 5_56 (m，1H)，7·54 (d，1H)， 8·17 (d，1H) 466 199 3-|&gt;(7-氮雙環并 [2.2.1]庚-7-基）丙基磺 醯基]_Ν-[5·氟基-4-(2-甲基-3-丙-2-基-味唾 -4-基）♦ °定-2-基]-(1 α，5α，6α)·3·氮雙環 并[3.1.0]己烧-6-胺# 1.29 (m，4H)，1·60 (d，6H)， 1.71 (m，4H)，1.79 (s，2H)，1·97 (m，2H)，2.47 (t，2H)，2.59 (s， 3H)，2.83 (d，1H)，3.11 (m， 2H)，3.26 (s，2H)，3.46 (m， 2H)，3.73 (d，2H)，5.08 (d，1H)， 5.56 (m，1H)，7·54 (d，1H)， 8.17 (d，1H) 518 於環境溫度下進行7天 #於95°C下進行2天 實例200 4-[[4-(3-環戊基-2-甲基-味嗤_4-基)-5-氟-嘴咬-2-基]胺基】’、氮p比 啶小羧酸苄酯 將（E)-l-(3_環戊基-2-曱基-味唑斗基）_3_二甲胺基-丙；烯小 120858 -139- 200811169 酮（方法13 ; 6 7夯，27 1臺莖且、、、兵丄γ u 兄以· i笔旲耳）添加至無水乙腈（14〇毫升） 中並冷卻至-2C，然後分次添加SelectfluorTM(12克，33.9毫 莫耳），保持溫度在_2°C下。接著，使反應物溫熱至環境溫 度，並攪拌30分鐘，然後，使其蒸發至乾酒。添加飽和NaHc〇3 水溶液，接著以DCM (3 X 200毫升）萃取水層，脫水乾燥， 並在真空中移除溶劑，而產生黃色膠質。將膠質與‘胺基 碳亞胺醯胺基六氫吡啶小羧酸芊酯（方法14 ; 8·2克，29·8毫 莫耳）添加至2-甲氧基乙醇（1〇〇毫升）中，並於回流下加熱16 小時。然後，使反應物蒸發至乾涸，添加飽和NaHC〇3水溶 液，接著以DCM (3 X 150毫升）萃取，脫水乾燥，及在真空 中移除溶劑’而產生黏稠黑色油。於矽膠上藉急驟式層析 純化’以DCM中之0-5% MeOH溶離，獲得固體，使其溶於DCM 中’添加乙腈’然後t艾恢地於真空中移除DCM，以沉殿固 體。過濾沉澱物，並在真空中乾燥，而得標題化合物，為 無色固體。NMR (400.132 MHz，CDC13) 1.40-1.48 (m，2H)，1.62-1.73 (m，2H)，1.88-2.05 (m，6H)，2.11-2.19 (m，2H)，2.57 (s，3H)，2.97-3.03 (m， 2H)，3.85-3.94 (m，1H)，4.14 (d，2H)，4·90 (d，1H)，5.14 (s，2H)，5.57-5.62 (m，1H)，7.29-7.37 (m，5H)，7.51 (d，1H)，8.15 (d，1H) ; MH+ 479· 實例201 4-(3-環戊基-2-甲基-哺峻-4-基)-5-氟-Ν·(4-六氫峨唆基）,咬胺 於40°C及5巴壓力之氫下，將EtOH (100毫升）中之4-[[4-(3-玉哀戊基-2-甲基-味嗤_4_基）·5-氟-喷σ定-2-基]胺基]六氫P比咬小魏 酸芊酯（實例200 ; 4.5克，11.3毫莫耳）與10% Pd/C (0.45克）攪 拌16小時。使反應混合物經過石夕藻土過濾，並移除溶劑， 120858 -140- 200811169 而產生蠟狀固體。使其通過短矽膠管柱，以DCM中之3.5-10% MeOH溶離。使所獲得之膠質自熱乙腈再結晶，而得標題化 合物。NMR (400.132 MHz，CDC13) 1.41 (ddd，2H)，1.65-1.72 (m，2H)， 1.89-2.05 (m，6H)，2.11-2.21 (m，2H)，2·58 (s，3H)，2.67-2.74 (m，2H)， 3.11-3.14 (m，2H)，3.77-3.86 (m，1H)，4.94 (d，1H)，5.61-5.73 (m，1H)，7.51 (d，1H)，8.14 (d，1H) ; MH+ 345. 實例202 4-(3-環戊基_2-甲基-味峻-4-基)-5-氟-N-(l-甲基確酿基-4·六氫π比 啶基）嘧啶-2-胺 標題化合物係以類似實例115之方式，並於類似規模下利 用4-(3-ί衣戍基-2-甲基-味嗤-4-基）-5-氟-N-(4-六氮p比σ定基）u密σ定 胺（實例201)作為起始物質而製成。NMR (400.132 ΜΗζ， CDC13) 1.6M.73 (m5 4H)? 1.89-2.08 (m5 4H), 2.13-2.17 (m? 4H)? 2.58 (s, 3H)，2.81 (s，3H)，2.91 (dt，2H)，3.74-3.77 (m5 2H)，3.83-3.92 (m，1H)，4.98 (d，1H)，5.53 (五重峰，1H)，7.51 (d，1H)，8.16 (d，1H) ; MH+ 423. 實例203至204 下述實例係以類似實例139之方式，並於類似規模下利用 4-(3-環戊基-2-甲基-咪唑-4-基&gt;5-氟K4-六氫吡啶基）嘧啶-2-胺（實例201)作為起始物質而製成。 120858 -141- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 203 4-(3-ί辰戍基-2-甲基_ 咪唑-4-基）-5-氟-N-[l-(2-四氮ρ比洛-1-基乙 基石黃醯基）-4-六氫外匕 啶基]嘧啶-2-胺 1.57-1.72 (m，4H)，1.79-1.83 (m，4H)，1.85-2.19 (m，8H), 2.54-2.58 (m，7H)，2.90-3.02 (m，4H)，3.14-3.18 (m，2H)， 3.76-3.79 (m，2H)，3.83-3.92 (m，1H), 4.93 (d，1H)，5·53 (五重峰，1H)，7.50 (d5 1H)， 8.16 (d，1H) 506 204 4_(3_環戊基-2-甲基-咪唑-4-基）-N-[l-(2-二 甲胺基乙基磺醯 基）-4-六氫吡啶基]-5-氟密唆-2-胺 1.57-1.70 (m，4H)，1.88-2.19 (m，8H)，2.28 (s，6H)，2.58 (s， 3H)? 2.76 (t? 2H)5 2.96-3.02 (m5 2H)，3.10 (t，2H)，3.76-3.79 (m， 2H)，3.85-3.94 (m，1H)，4.96 (d，1H)，5.54 (五重峰，1H)， 7.50 (d，1H)，8.16 (d，1H) 480 實例205 N-[l-(3-氣基丙基確醯基）-4_六氫峨咬基】-4-(3-環戊基_2-甲基_ 咪唑-4-基）-5_氟-嘧啶_2胺 標題化合物係以類似實例143之方式，並於類似規模下利 用4-(3-環戊基-2·甲基-味α坐-4-基）-5·氟-N-(4-六氫巧1：。定基）喷咬 -2-胺（實例2〇1)作為起始物質而製成。MH+ 487. 實例206至207 下列化合物係藉由實例144之程序，並於相同規模下，利 用N-[l-(3-氯基丙基磺醯基）冰六氫吡啶基]冰(3_環戊基！甲義 -味唑-4-基）-5H咬-2-胺（實例205)與適當胺製成。 120858 142- 200811169 實例 化合物 NMR (400.132 MHz, CDC13) m/z 206 4-(3-環戊基-2-甲基-咪唑-4-基）·Ν-[1-(3-二 甲胺基丙基磺醯 基）-4-六氮Ρ比σ定基]-5-氟-嘧啶-2-胺 1.57-1.72 (m，4H)5 1.92-2.17 (m，10H)，2·22 (s，6H)，2.39 (t5 2H)，2.58 (s，3H)，2.95-3.02 (m， 4H)5 3.77 (d5 2H)? 3.83-3.92 (m，1H)，5.01 (d，1H)，5.54 (五重峰，1H)，7.50 (d，1H)， 8_16 (d，1H) 494 ^ 207 4-(3-ί哀戍基-2-甲基_ 咪唑-4-基）-5-氟_Ν-[1-(3-四氫吡咯_1_基 丙基石頁酿基）-4-六鼠 吡啶基]嘧啶-2-胺 1.62-1.74 (m，4H)，1.89-2.19 (m，12H)，2.30 (五重峰，2H)， 2.57 (s, 3H)5 3.01-3.09 (m5 8H)? 3.20 (t，2H)，3·76_3·80 (m，2H)， 3.86-3.95 (m，1H)，5·21 (d， 1H), 5·54 (五重峰，1H)，7.49 (d，1H)，8.15 (d，1H) 520 ^ 實例208 3-[[5-敗基·4_(2-甲基_3_丙·2_基-咪唑冬基），啶：基】胺基卜氮 七園烷小羧酸第三-丁酯 將3-胺基碳亞胺醯胺基一氮七圜烷小羧酸第三_丁酯（方 法15 ·，192毫克，〇.75毫莫耳）與（2办3_(二甲胺基氟基·丨七· 異丙基-2-甲基-1Η-咪唑-5-基）丙-2-烯-1_酮（在W007015064中之 方法1)(360毫克，L50毫莫耳）在2_甲氧基乙醇（1〇毫升）中之 溶液’於回流下加熱24小時。然後蒸發溶劑，並使殘留物 於矽膠上藉急驟式層析純化，以〇-5%Me〇H/DCM溶離，而得 枯題化合物，為無色固體⑽毫克，15%)。nmr (棚丨^應^， CDC13) 1.43 (m? 16H)5 1.65 (m5 4H)5 1.92 (m5 1H)5 2.52 (s? 3H)? 3.06 (m, 1H)，3.39 (m，1H)，3·63 (m，2H)，4.08 (m，ih)，5·5〇 (m，1H)，7 19 (s，1H)， 7.44 (d，1H)，8.06 (s，ih) ; m/Z433. ’ 實例209 Ν·[5-氟基-4-(2-曱基各丙：基 唑冰基）嘧啶-2-基]一氮七 圜 120858 -143 . 200811169 烷-3-胺 於環境溫度下，將三氟醋酸（〇·5毫升）添加至3-[[5-氟基 冰(2-甲基各丙冬基-味唑-4_基）嘧啶各基]胺基]一氮七圜烷+ 羧酸第三-丁酯（實例2〇8; 48毫克，0.11莫耳）在DCM (1.0毫升） 中之經攪拌溶液内。2.5小時後，蒸發溶劑，而得標題化合 物，為膠質（103毫克）。M/z 333· 實例210 义[5_氟基-4-(2-甲基-1-丙-2-基-味唾_4_基）喊唆_2_基]小甲績醯 基-一氮七圜烧-3-胺 於壤境溫度下’將氣化曱烧績S篮（0.013毫升，〇·17毫莫耳） 與三乙胺（0.046毫升，0.33毫莫耳）添加至N_[5_氟基冬(2_甲基 _3_丙_2_基_味唑基）續啶基]一氮七圜烧各胺（實例2〇9; 1〇3 耄克）在DCM (2宅升）中之經攪拌溶液内。4小時後，添加另 外之氯化曱烧磺醯（0.013毫升，0.17毫莫耳），並將反應混合 物在環境溫度下攪拌64小時。蒸發溶劑，獲得膠質，使其 溶於MeOH中，並裝載於SCX-2管柱上。將管柱以Me〇H洗滌 三次’然後以2M NHs/MeOH溶離。使用rphplc另外純化， 獲得標題化合物，為無色固體（7毫克，16%)。_ (4〇〇132 MHz，MeOH) 1.65 (d5 6H)，1.82 (m，6H)，2.G3 (m，2H)，2_81 (s，3H)，2.87 (s，3H)，3·38 (m，4H)，4.16 (m，1H)，5.53 (m，1H)，7·84 (s，1H)，8.40 (s， 1H) ； m/z 411. 起始物質之製備 方法1 4-胺基碳亞胺醯胺基六氫峨唆小叛酸爷醋 120858 -144 - 200811169 使4-胺基六氫吡啶小羧酸苄酯（25克，ι〇6·7毫莫耳）、吡唑 •1-叛醯亞胺醯胺（31.3克，213.4毫莫耳）及TEA (30毫升）溶於 MeCN (500毫升）中，並在60°c下加熱過夜。18小時後，蒸發 溶劑。使所形成之橘色殘留物於飽和NaHC〇3水溶液（5〇〇毫 升）與DCM (500毫升）之間作分液處理。分離dcm層，且藉 過渡收集被包含在其中之微細沉澱物，然後以少量DCM洗 滌’及在真空下乾燥，而產生白色固體（3〇8克，1〇〇%)。nmr (400.132 MHz) 1.31 (m，2H)，1.82 (m，2H)，2·96 (m，2H)，3.57 (m，1H)， 3·92 (m，2H)，5.08 (s5 2H)，7·35 (m，5H)，7.96 (s，2H)_ 方法2 胺基碳亞胺醯胺基四氫吡咯小羧酸第三_丁酯 於3-胺基四氫吡咯小羧酸第三-丁酯（3 〇3克，16·27毫莫耳） 在乙腈（60宅升）中之溶液内，添加ΤΕΑ (4·7毫升，32 75毫莫 耳），接著為111_峨嗤小竣甲脒鹽酸鹽（4·8克，33.72毫莫耳）。 將反應混合物加熱至65°C (内部溫度），歷經6小時，然後留 置冷卻過夜。蒸發反應混合物，而產生帶有鮭魚粉紅色之 黏稠油，使其在飽和NaHC〇3水溶液（75毫升）與DCM⑺毫升） 之間作分液處理。接著，使混合物激烈振盪，且使其靜置 10分鐘，然後再一次振盪，及藉過濾收集所形成之固體。 將濾餅以DCM、水洗滌，並在抽吸下抽取乾燥〜3〇分鐘，接 著轉移至真空乾燥器，且留置乾燥度過週末，而得標題化 合物，為灰白色固體（2·14 克，58%)。NMR (400.132 MHz) M1 (s， 9H)，1.78 (m，1Η)，2·09 (m，1H)，3.07 (m，1H)，3.15-3.51 (m，4H)，4·03 (m， 1H)，7.01-8.81 (m, 3H)· 120858 -145· 200811169 方法3 4-嗎福琳-4-基丁酸鹽酸鹽 將4-溴基丁酸乙酯（67毫升，〇·5Μ)逐滴添加至嗎福啉（175 耄升，2Μ)在無水甲苯（1升）中之溶液内。將反應混合物於 60°C下攪拌4小時，然後在環境溫度下16小時。在下， 過濾反應混合物’並蒸發濾液。將所形成之物質以6〇-8〇輕 油研製，並蒸發，而得橘色油（91.4克），使其在減壓下蒸餾， 獲得透明油（73.2克），沸點90·2ΐ /3-4毫米Hg。將所形成之油 於回流下，在18% HC1 (水溶液）（1升）中加熱16小時。蒸發 酸，留下黏性固體，其在以醚研製時，獲得白色固體（75·25 克），使其自冰醋酸/丙酮再結晶，而得標題化合物，為白 色結晶性固體（56.43克，53%)，溶點181-3°C。 方法4 4-(2-曱基-3-丙_2-基_喃嗤-4-基）咳咬_2醇 於惰性大氣下，使4-(2-甲基各丙冬基-味唑斗基）,密啶冬胺 (方法 39，WO2003/076436，5 克，23 毫莫耳）溶於 70% AcOH_ 水（145毫升）中。於環境溫度下，逐滴添加水（1()毫升）中之 亞硝酸鈉（5.52克，80毫莫耳），歷經5分鐘期間，導致溫和 放熱。將反應混合物慢慢地加熱至60〇c，並在此溫度下保 持3小時。使反應混合物冷卻至環境溫度，並以 水溶液中和至pH 7，以EtOAc (250毫升X 5)萃取，且使合併 之萃液脫水乾燥，及蒸發，而得標題化合物，為灰白色固 體。（8.2 克 43%)。NMR (400.132 MHz，CDC13) 1.51 (d，6H)，2.03 (s，3H)， 2.54 (s，3H)，5.93 (m，1H)，6.60 (d，1H)，7.57 (m，2H) ; MH+ 219. 120858 -146- 200811169 方法5 2-氣基-4-(2-甲基-3-丙·2_基-味嗤-4-基）嘯咬 將4-(2-曱基-3-丙-2-基喃唾-4-基）喷π定-2_醇（方法4 ; 8.2克， 29.4毫莫耳）、氯化磷醯（120毫升）及五氯化磷（6·6克），在回 流加熱下合併，歷經18小時。蒸發出過量氯化磷醯，並使 殘留物溶於DCM中，且在冰與水中攪拌。藉由添加4〇%氫 氧化鈉水溶液使混合物來到ρΗ η。將有機物質與水相分 離，並以鹽水洗滌有機相，脫水乾燥，及蒸發。使所形成 之物質溶於DCM中，並於矽膠上層析，在〇-5% Me〇H/〇CM之 淺梯度液上溶離。合併含有產物之溶離份，並蒸發，而得 標題化合物，為淡褐色膠質（5·8克，84%)。^^(4〇〇132乂他) 1·53 (d，6Η)，2.50 (s，3Η)，5.27 (m，1Η)，7.72 (s，1Η)，7·79 (d，1Η)，8.62 (d， 1H) ； MH+ 237. 方法6 2,5_一氣-4_(2-甲基_3_丙：基_味唑_4_基）嘴啶 使5氣基-4-(2-甲基丙基-味唑冰基）嘧啶_2_胺（方法5， j W005/075461巾，5克，19 9毫莫耳）溶於醋酸⑺毫升）/水（3〇 :升）中’並慢慢添加水（8毫升）中之亞硝酸鈉（2.75克，39.8 毫莫耳)。將反應物於環境溫度下攪拌1〇分鐘，然後在6(TC …、3小時。然後，使反應物蒸發至乾涸，添加NaHC03 W液至PH9 ’並以Dcm(3x⑽毫升）萃取水層。使合併之 有機物質脫水乾、择，β ，、過濾，且在真空中移除溶劑，而得固 體’使其溶於最少量之劫7拉士 里之熱乙腈中，於冷卻時，獲得白色固 體。將固體添加至梟养 乳化磷醯（50 t升）中，並於80°C下加熱1 120858 •147- 200811169 小時。使反應混合物蒸發至乾涸，接著以飽和NaHC〇3水溶 液小心地使反應淬滅至pH 8。使反應物濃縮至乾涸，而得 標題化合物，為黃色固體（3·47克，64%)。NMR (400.132 MHz， CDC13) 1.58 (d，6H)，2·61 (s，3H)，4·96 (七重峰，1Η)，7·80 (S，1H)，8.58 (s，1Η) ; ΜΗ+ 273· 方法7 5-氟基-4-(2•曱基-3-丙_2_基味唑_4-基）吻啶-2-醇醋酸鹽 於惰性大氣下，使5-氟基-4-(2-甲基_3_丙-2-基^米唑冬基）, 啶-2-胺（在W02006/064251中之方法17 ; 4克，17毫莫耳）溶於 70% AcOH_水（108毫升）中。於環境溫度下，逐滴添加水（8毫 升）中之亞硝酸鈉（4.08克，59.2毫莫耳），歷經5分鐘。使反 應混合物慢慢地溫熱至60°C。3小時後，使反應混合物冷卻， 然後以40% NaOH水溶液中和至pH 7。以EtOAc (300毫升X 6) 萃取水層，使合併之有機物質脫水乾燥，過濾，及蒸發， 而得標題化合物，為黃色固體（4.07克，81%)。NMR (400.132 MHz) 1.48 (d，6H)，1·91 (s，3H)，2·50 (s，3H)，5.44 (m，1H)，7.47 (d，1H)， 8.29 (d? 1H) ； MH+ 237. 方法8 2-氣基-5·氟基-4-(2曱基_3·丙-2-基-味嗤-4_基），咬 使5-氟基冰(2-甲基-3-丙-2-基-咪唑-4-基）嘧啶-2-醇醋酸鹽 (方法7 ; 4克，13.5毫莫耳）懸浮於氯化磷醯(25毫升）中，並 加熱至90°C，歷經3.5小時。使反應混合物在真空中濃縮， 然後，使殘留物溶於DCM (25毫升）中，並與冰/水（50毫升） 一起攪拌。使混合物在冰水浴中冷卻，以40% NaOH水溶液 120858 • 148 - 200811169 中和至pH 8，接著添加水與DCM (50毫升），並分離有機層。 將水層以DCM (75毫升）萃取，然後，將合併之有機物質以 鹽水洗滌，脫水乾燥，過濾，及蒸發，獲得褐色油。於矽 膠上藉急驟式層析純化，以50% EtOAc/異己烷溶離，獲得標 題化合物，為黃色油，其係於靜置時結晶（2.84克，83%)。 NMR (400.132 MHz，CDC13) 1.54 (d，6H)，2.54 (s，3H)，5.34 (m，1H)，7.69 (m，1H)，8.32 (m，1H) ; MH+ 255. 方法9 N-環戍基-5-甲基-l，2-v号嗤_4-胺 將5-甲基-1，2_呤唑-4-胺鹽酸鹽（20克）、環戊酮（13.9毫升）及 醋酸鈉（12.3克）添加至MeOH (200毫升）中，並於0°C下攪拌1 小時。慢慢添加NaCNBH3(11.5克），歷經20分鐘，同時保持 溫度低於0°C。在添加完成後，使反應混合物溫熱至環境溫 度，並攪拌16小時，然後於真空中移除溶劑。使所獲得之 固體溶於飽和NH4C1水溶液（1〇〇毫升）中，並以醚（2 X 200毫 升’接著為1 X 100毫升）萃取。使合併之有機萃液脫水乾燥， 過濾’且在真空中移除溶劑，而得黃色油。使油於矽膠上 藉管柱層析純化，使用異己烷中之1〇_5〇〇/0醚作為溶離劑。 於真空中移除溶劑，而得標題化合物，為黃色油（17·2克）。 NMR (300.072 MHz，CDC13) 1.37-1.47 (m，2Η)，1.54-1.79 (m5 4Η)， 1·83-1·94 (m，2H)，2.31 (s，3H)，3·51 (五重峰，1H)，8.03 (s5 1H); m/zl67· 方法10 N-環戊基_N-(5-甲基_l，2_哼唑-4-基）乙醯胺 將醋酸酐（18·9毫升）分次添加至N-環戊基-5-曱基-1，2_噚唑 120858 -149- 200811169 胺（方法9 ’ 16·〇克）在醋酸（ι6〇毫升）中之經擾拌溶液内， 歷經20分鐘。i小時後，於真空中移除溶劑，並將所形成之 漿液以K2C03水溶液（50毫升，注意·· c〇2釋出）處理。以匪 (3 X 50笔升）萃取水層，使合併之有機物質脫水乾燥（n^s〇4) ，並於真空中移除溶劑。使所獲得之固體在高真空下乾燥， 而得標題化合物，為黃色固體（19.0克）。NMR (300.074 MHz) 1.08-1.24 (m, 2H)? 1.4M.51 (m, 4H)? 1.69 (s5 3H), 1.74-1.80 (m5 2H)5 2.33 (s，3H)，4_77 (五重峰，ih)，8·64 (s，1H) ; MH+ 209. 方法11 N-[(E)-1-胺基_3-酮基·丁小稀_2_基】具環戊基_乙醯胺 將N-環戊基_N-(5-f基-異噚唑斗基）_乙醯胺（方法1〇 ; 19 克，91¾莫耳）與1〇%鈀/碳克），於氫大氣下，在增加壓 力（4大氣壓）下，於EtOH中一起攪拌。然後過濾反應物，並 在真空中移除溶劑。將DCM，接著添加醚至殘留物中，並 過濾反應物，而得標題化合物，為無色固體（16克，84%)。 NMR (300.074 MHz) 1.19-1.49 (m? 6H), 1.59-1.80 (m5 5H)? 2.06 (s5 3H), 4·44 (五重峰，1H)，6.84 (d，2H)，7.59 (t，1H) ; MH+ 211. 方法12 1_(3-環戍基_2-甲基-味嗤_4_基）乙酮 將N-[(E)-1-胺基-3-酮基-丁小烯-2-基]-N-環戊基-乙醯胺（方 法11 ; 16.0克）與NaOH (3.66克）添加至EtOH (200毫升）中，並 於回流下加熱4小時。添加NI^Cl (6.11克），並將混合物在環 境溫度下攪拌16小時，然後於真空中濃縮。添加醚（35〇毫 升），將混合物攪拌10分鐘，然後過濾，及在真空中濃縮。 120858 -150- 200811169 使所獲得之黃色油在減壓（0·55毫巴/1〇(rc )下蒸餾，而得標 題化合物’為透明油（10 08克）。丽汉（4〇〇 132 MHz，cdC13) 1.66-1.71 (m，2H)，1.97-2.04 (m，6H)，2·45 (s，3H)，2.50 (s，3H)，5·22 (五 重峰，1H)，7.73 (s，1H) ; MH+ 193· 方法13 (E)-l_(3-環戊基_2_甲基味唑冰基)各二甲胺基_丙_2_稀小酮 將1·(3-環戊基-2-甲基-哺唑-4-基）乙酮（方法12 ; 10.08克）與 DMF-DMA (17.9毫升）添加至DMF (150毫升）中，並於130°C下 加熱ό小時。於真空中移除溶劑，並添加dcm (10毫升），接 著為鱗（100毫升）。使混合物音振1〇分鐘，然後過濾，且乾 燥’而得標題化合物，為黃色固體（9.74克）。NMR (400.132 ΜΗζ， CDC13) 1.61-1.72 (m，2Η)，1.91-2.14 (m，6Η)，2·49 (s，3Η)，2·99 (s，6Η)， 5.35 (五重峰，1Η)，5·52 (d，1Η)，7·48 (s，1Η)，7·62 (d，1Η) ; ΜΗ+ 248. 方法14 4-胺基碳亞胺醯胺基六氫u比咬小貌酸爷g旨 使4-胺基六氫p比唆-1-魏酸爷g旨（2〇克，85.5毫莫耳）與TEA (24毫升，171毫莫耳）溶於乙腈（300毫升）中，然後添加m_ 咐嗤小羧醯胺（25克，171毫莫耳），並將反應物於65t下加 熱16小時。接著，使反應混合物蒸發至乾涸，並以飽和碳 酸鈉水溶液（200毫升）使反應淬滅，以DCM (3 X 150毫升）萃 取，使合併之有機物質脫水乾燥，並在真空中移除溶劑， 而產生橘色固體。添加乙赌（100毫升），並於65°C下檟;掉20 分鐘，使所形成之漿液冷卻，且過濾，而得標題化合物， 為無色固體。NMR (400.132 MHz) 1.27-1.36 (m，2H)，1.81-1.83 (m， 120858 -151 - 200811169 2H), 3·18-3·55 (m，3H)，3.93 (d，2H)，5.08 (s，2H)，7.30-7.41 (m，5H)， 7.60-8.55 (brs, 4H) ； MH+ 277 方法15 3-胺基碳亞胺醯胺基—氮七g n缓酸第三-丁醋 將吡唑-1-羧醯亞胺醯胺鹽酸鹽（739毫克，5 〇4毫莫耳）添 加至弘胺基一氮七圜烷+羧酸第三-丁酯（541毫克，2·52毫莫 耳）與二乙胺（0.7毫升，5·04毫莫耳）在乙腈（15毫升）中之經 撥拌/谷液内將此合物於回流下加熱3.5小時，然後冷卻至 裱境溫度，過濾，並以乙腈洗滌，並在高真空下乾燥，而 得標題化合物，為無色固體（179毫克，28%)。在真空中蒸發 乙腈濾液’使所獲得之膠質溶於DCM中，並添加飽和碳酸 氫鈉水溶液’且將混合物留置於環境溫度下16小時。過濾 已沉殿之固體，並在真空中乾燥，獲得另外之標題化合物， 為無色固體（192 毫克，30%)。NMR (400.132 MHz) 1.41 (m，9H)，1.68 (m，3H)，3.37 (m，8H)，7·81 (s，2H). 實例211 下文係說明含有式（I)化合物或其藥學上可接受鹽或活體 内可水解酯（後文化合物X)之代表性醫藥劑型，在人類中用 P治療或預防用途：- ⑻：片劑I 毫克/片劑 化合物X 100 乳糖Ph.Eur 182.75 葬羧甲基纖維素鈉 12.0 玉米澱粉糊劑（5% w/v糊劑） 2.25 硬脂酸鎂 3.0 120858 -152- 200811169 (b):片劑II 毫克/片劑 化合物X 50 乳糖Ph.Eur 223.75 交聯羧甲基纖維素鈉 6.0 玉米澱粉 15.0 聚乙稀基四氫卩比嘻酮（5% w/v糊劑） 2.25 硬脂酸鎂 3.0 (c):片劑 III 毫克/片劑 化合物X 1.0 乳糖Ph.Eur 93.25 交聯羧甲基纖維素鈉 4.0 玉米澱粉糊劑（5% w/v糊劑） 0.75 硬脂酸鎂 1.0 (d):膠囊 毫克/膠囊 化合物X 10 乳糖Ph.Eur 488.5 硬脂酸鎂 1.5 ⑻：注射液I (50毫克/毫升） 化合物X 5.0% w/v 1M氫氧化鈉溶液 15.0% v/v 0.1M鹽酸 (以調整pH至7·6) 聚乙二醇400 4.5% w/v 注射用水 至 100% 120858 -153 - 200811169 (¢):注射液II 10毫克/毫升 化合物X 1.0% w/v 磷酸鈉BP 3.6% w/v 0.1M氫氧化鈉溶液 15.0% v/v 注射用水 至 100% (g):注射液III (1毫克/毫升，經緩衝至pH 6) 化合物X 0.1% w/v 磷酸鈉BP 2.26% w/v 擰檬酸 0.38% w/v 聚乙二醇4〇〇 3.5% w/v 注射用水 至 100% 註 上述配方可藉由醫藥技藝上所習知之習用程序獲得。片 劑⑷-(c)可藉習用方式被腸溶性物質塗覆，例如提供纖維素 醋酸S太酸醋之塗層。 120858 -154-Stir at ambient temperature for 9G minutes. The solvent was evaporated and the residue was taken in DCM eluting with EtOAc EtOAc EtOAc. The fractions containing the product were combined and evaporated to give a clear gum. Ethyl ether was added to the gum and evaporated to give the title compound, &amp; nmR (4〇〇·132 read 2, CDCl3)]% (m,iih), work 48 (9) 6H)5 1.97 (m5 2H)? 2.50 (s? 3H)5 2.85 (m5 2H)? 3.93 (m? 3H ), 4.88 (m5 1H)3 5.52 (m,1H), 6.67 (d,1H), 7.25 (s,1H), 8.13 (d,1H). Example 35 N-(l-Vinylsulfonyl-4 -hexahydropyridyl)_4_(2·methyl_3_propan-2-yl-isoxazole_4_yl)pyrimidin-2-amine Add TEA (0.7 ml, 5 mmol) to 4_(2 _Methyl_3_propan-2-yl- oxazolidine-N-(4-hexahydropyridinyl)-pyridinamine (Example 2; 5 〇〇 mg, 17 mmol) in DCM (25 Within the solution in ML). Chlorinated 2-chloroethanesulfonate (0.26 ml, 2.5 mmol) in a small volume of dcm was added dropwise to the solution to give a color change from colorless to yellow. Upon completion of the addition, a solid has formed. After 3 minutes, the solid matter was filtered off. The filtrate was diluted with DCM and washed with water. The aqueous phase was extracted with DCM and the combined organics were washed with brine, dried and evaporated. The resulting material was dissolved in dcm and chromatographed on silica gel eluting with a gradient of 0-10% MeOH / DCM. The title compound was obtained as an off-white solid (218 mg, 34%). MH+ 391. Example 36 Ν-[1-[2-(4-methylhexahydropyridin-4-yl)ethylsulfonyl] hexahydropyridinyl-(2-methylpropan-2-yl) ·Nanjun-4·base), bite_2-amine 120858-84- 200811169 Add 1-methylhexahydropyridinium (0.06 ml, 〇·54 mmol) to N-(1-ethlylsulfonate) Mercapto-4-hexahydropyridyl) ice (2-methylpropan-2-yl^moxazolidine) 0-mididine-2-amine (Example 35, 72 mg, 0.18 mmol) in hydrazine: i THF/DCM (3 ml) t solution. The reaction mixture was stirred at ambient temperature for 72 hours. The solvent was evaporated <RTI ID=0.0></RTI> and the title compound was purified by EtOAc EtOAc. NMR (400.132 MHz, CDC13) 1_49 (d,6H),1·56 (m,2H),2.08 (m5 2H), 2.22 (s,3H), 2.39-2.46 (m,8H),2_50 (s,3H ), 2.77 (m, 2H), 2·93 (m, 2H), 3.06 (m, 2H), 3.71 (m, 2H), 3.90 (m, 1H), 4.88 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H), 8.14 (d? 1H); MH+ 491. Examples 37-62 The following compounds were prepared by the procedure of Example 36 and used at the same scale. Made of amine starting materials. Example compound NMR (400.132 MHz, CDC13) m/z 37 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-oxime [1-(2-tetragas ρ ratio) -1- ylethyl group * yl)-4-hexahydro ρ ratio octyl] ytidine 2 -amine 1.48 (d, 6H), 1.56 (m, 2H), 1.74 (m, 4H), 2.08 ( m,2H), 2.48 (m, 7H), 2.85 (m, 2H), 2.93 (m, 2H), 3.09 (m, 2H), 3.71 (m, 2H), 3.89 (m, 1H), 4.88 (m ,1H),5·46 (m, 1H), 6.69 (d,1H), 7.24 (s,1H), 8.14 (d,1H) 462 38 N-[l-[2-(2-methoxy B Amino)ethylsulfonyl]-4-hexahydropyridinyl]-4-(2-methyl-3-propan-2-yl-m-amino-4-yl)-glycol-2-amine 1·48 (d,6H), 1.57 (m, 2H), 2.08 (m, 2H), 2.50 (s, 3H), 2.74 (m, 2H), 2.92 (m, 2H), 3.05 (m, 4H), 3.29 ( s,3H), 3.42 (m,2H), 3.71 (m,2H),3·90 (m,1H), 4.89 (m, 1H), 5.46 (m,1H),6·69 (d,1H) , 7.24 (s,1H), 8.14 (d,1H) 466 120858 -85 _ 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 39 4-(2-mercapto-3-propan-2-yl-imidazole -4-yl)-Ν·[&gt;(2-thio-formin-4-ylethyl-stone-branched)-4-hexahydroquinone σ定基]pyrimidine-2-amine 1.49 (d,6H),1·57 (m,2H),2·09 (m,2H),2.52 (s,3H),2·61 (m, 4H),2 ·70 (m,4H),2·81 (m,2H), 2.93 (m,2H), 3.04 (m,2H),3·70 (m,2H),3.91 (m,1H),5.00 (m , 1H), 5.45 (m, 1H), 6.69 (d, 1H), 7.26 (s, 1H), 8.15 (d, 1H) 494 40 4-(2-methyl-3-prop-2-yl) -4--4-yl)-N-〇[2-(l-hexahydro sigma)ethyl stellate]-4-six ρ ϋ定定] shouting-2-amine 476 41 N-[l -[2-(indolyl-propan-2-yl-amino)ethylsulfonyl]-4-hexahydrop-butyl]-4-(2-methyl-3-propan-2-yl- .米°坐-4-基),2,0,0,0,5,5 , 2.79 (m, 3H), 2.91 (m, 2H), 3.02 (m, 2H), 3.72 (m, 2H), 3.89 (m, 1H), 4.89 (m, 1H), 5.47 (m, 1H), 6.69 (d,1H), 7.24 (s,1H), 8.14 (d, 1H) 464 42 N-[l-[2-(aza-tetracyt-yl)ethyl)]-6·hexahydro Pyridyl]-4-(2-methyl-3-propan-2-yl-N-oxan-4-yl)pyrimidin-2-amine 448 43 4-(2-methyl-3-prop-2-yl) -imidazole-4.yl)-oxime-[1·(2-morpholine-4-ylethylsulfonyl)-4-hexahydropyridinyl] p-deni-2-amine 478 44 N-[l -[2-(4•Methyl hexahydropyridyl)ethylsulfonyl M-hexahydro? σ 定 ] -4- -4- -4- -4- -4- -4- ), 1.48 (d, 6H), 1.56 (m, 4H), 1.99 (m, 2H), 2.08 (m, 2H), 2.50 (s, 3H), 2.77 (m, 4H), 2.93 (m, 2H), 3.08 (m, 2H), 3.71 (m, 2H), 3.90 (m, 1H), 4.90 (m, 1H), 5.46 (m, 1H), 6.69 (d, 1H), 7.24 (s, 1H) ), 8.14 (d, 1H) 490 120858 -86- 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 45 N-〇[2-(-azadec-7-yl)ethyl stellite] -4-hexanitrogen p sigma]-4-(2-methyl-3.propan-2-yl) oxime-2-amine 490 46 N-[l-(2-diethylamino-B Basis acid)-4-hexanitrogen p sigma]-4-(2·indolyl-3-propan-2-yl-miso-4-yl) sigma 2-amine 464 47 4-[ 2-[[4-[[4-(2·曱-yl-3-propan-2-ylmitot-4-yl) σ 唆 唆-2-yl]amino]-1-hexa-purine 匕 定 定] 醢 ] ] 乙基 ] ] ] ] ] ] ] ] 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 1.4 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮 酮), 2.87 (m, 2H), 2.95 (m, 2H), 3.06 (m, 2H), 3.12 (s, 2H), 3.32 (m, 2H), 3.70 (m 2H), 3.92 (m, 1H), 5.04 (m, 1H), 5.45 (m, 1H), 5.93 (s, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8_14 (d, 1H) 491 48 4-(2-Methyl-3-propan-2-yl- sulphate-4-yl)-N-[l-[2-(l,4-oxo-7-yl-4-yl) Ethylsulfonyl]-4-hexanitrozide σ determinate] pyrimidine-2-amine 492 49 N-[l-[2-[(3R)-3-fluoro-tetrahydropyrrole-1·yl]ethyl sulfonate Styrene]-4-hexanitrogen to sigma]-4-(2-methyl-3-propan-2-yl-imidazolidinyl)pyrimidin-2-amine 480 50 N-[l-[2-( 4-_Fluoro-1-hexahydroexopurinyl)ethyl decyl]-4-hexahydroindole]-4-(2-methyl-3-propan-2-yl-m-methane-4 -Based) β-Bite-2-Amine 494 120858 -87- 200811169 Example Compound NMR (400.132 MHz, CDC13) m/z 51 Ν_[1-[2-(7-Azabicyclo[2.2.1]hept-7 -yl)ethylsulfonyl]-4-hexahydroindole sigma]-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-amine 488 52 N- [l-[2-(cyclopropyl-methyl-amino)ethyl)]-4-hexanitro-b σ-decyl]-4-(2-methyl-3-prop-2-yl- Imidazole-4_yl) hydrazino-2-amine 462 53 Ν-[1-ρ·(cyclopropylmethyl-methyl-amino)ethyl-based base]-4-six ρ ratio 17 Fixed base]-4 -(2-methyl-3-propan-2-yl-4-imidazol-4-yl)pyrimidin-2-amine 476 54 1-[2-[[4-[[4-(2-methyl-3-propyl-) 2-基/乐ϋ坐-4-yl) succinyl-2-yl]amino]-1-hexahydro^: ϋ定基] 醯基]ethyl]hexahydropyridine-4-carboxyguanamine 1 ·49 (d,6H),1·59 (m,2H),1·70 (m,2H), 1.84 (m,2H),2.07 (m5 5H), 2.50 (s,3H), 2.75 (m, 2H), 2.87 (m, 2H), 2.96 (m, 2H), 3.06 (m, 2H), 3.68 (m, 2H), 3.92 (m, 1H), 4.93 (m, 1H), 5.21 (m, 1H) ), 5.46 (m, 2H), 6.69 (d, 1H), 7.24 (s, 1H), 8.13 (d, 1H) 519 55 1-[4-[2-[[4-[[4-( 2-methyl-3-propan-2-yl-flavor °-4-yl) succinyl-2-yl]amino]-1-hexahydro-b σ-based benzyl] ethyl] Hexanitrogen 11 well-1-yl]ethanone 519 56 1-[2-[[4-[[4-(2-methyl-3-propan-2-yl-ρm唆-4-yl), σ定-2-yl]amino]-1-hexazone 匕σ定基]sulfonyl]ethyl]-1,4-diaza heptane-5-酉 with 1.48 (d,6H), 1.58 (m, 2H), 2.09 (m, 2H), 2.50 (s, 3H), 2.60 (m, 6H), 2.92 (m, 4H), 3.03 (m, 2H), 3.24 (m, 2H), 3.69 ( m, 2H), 3.92 (m, 1H), 5.01 (m, 1H), 5.45 (m 1H), 5.86 (m, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8.14 (d, 1H) 505 120858 -88 - 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 57 1 -[4·[2-[[4-[[4-(2-methyl-3-propan-2-yl-πm-sup-4-yl))]]]]]]]]]]]] 1-hexahydroleaf b-yl]]-acid group] ethyl]-1,4-two mice, heptastatin-1-yl]acetamidine with 533 58 4-(2-mercapto-3-propan-2-yl _ imidazolyl-4-yl)-indole-[1·[2-(4-propyl-1-6-nine ρ ratio σ-based) ethyl-based brewing base]-4- six mouse outer 匕σ定基] shouting 唆2-Amine 518 59 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-N-[l-[2-(1,4-thiazol-7-yl) Ethyl sulphate]-4-hexanitropurine 匕 定 ] ] 唆 胺 胺 胺 胺 胺 胺 60 - 60 N-[l-[2-(2-azabicyclo[2·2·2]oct-2-yl) Ethylsulfonyl]-4-hexamethyl sigma]-4-(2-methyl-3.propan-2-yl-sodium sulphate-4-yl acyl-2-amine 502 61 1- [2-[[4-[[4-(2-methyl-3-propan-2-yl-)-[supple]-4-yl)-denyl-2-yl]amino]-1-hexa Pyridyl]sulfonyl]ethyl]hexanitroindole °-4-A gamma 501 62 N-[H2-[(3S)-3-fluoro-tetrazine-exo-bromo]ethyl fluorescene]- 4-hexanitrogen sigma]-4-(2-mercapto-3- Prop-2-yl- s-methoxy-4-yl)u-density-2-amine 480 Example 63 4-(2-methyl-propan-2-yl-imidazol-4-yl)-indole-(1· Methanesulfonyl-4-hexahydropyridyl) 120858 -89- 200811169 Pyridin-2-amine 2-chloro-4-(2-methylpropan-2-yl-imidazolidinyl)pyrimidine (Method 5 105 mg, 0.44 mmol, 1-methanesulfonylhexahydropyridin-4-amine TFA salt (Example 162, W004/069139, 156 mg, 0.53 mmol), DIPEA (0.23 mL, 1.33 mmol) The ear and IPA (3 ml) were combined and heated at 140 ° C for 30 minutes by microwave irradiation. The reaction mixture was passed through a bicarbonate cartridge carried by the polymer and then heated at 140 ° C for an additional 30 minutes. Another 1-indolesulfonylhexahydropyridin-4-amine TFA salt (Example 162, W004/069139, 220 mg, 0.76 mmol) was dissolved in MeOH and added to SCX pre-wetted with MeOH. -2 in the column. The column was rinsed with MeOH and the free base was dissolved in 2M ammonia in MeOH. The eluent was evaporated and the resulting material was added to a solution of DIPEA (0.2 mL) as a solution. The reaction was heated at 15 ° C for 5 hours. The precipitate formed was collected by filtration, dissolved in DCM and purified on silica gel eluting with 10% MeOH / DCM. The filtrate from the reaction was evaporated, dissolved in DCM, and purified eluting eluting eluting eluting eluting The fractions from the two columns containing the desired product were combined and evaporated to give the title compound as a white solid. (70 mg, 42%). NMR (400.132 MHz) 1.55 (d, 6H), 1.64 (m, 2H), 2.03 (m, 2H), 2·53 (s, 3H), 2.88 (m, 2H), 2·94 (s, 3H) , 3.64 (m, 2H), 3.89 (m, 1H), 5·67 (m, 1Η), 6·87 (d, 1H), 7.20 (s, lH), 7.40 (s, 1H), 8.27 (d , 1H) ; MH+ 379. Example 64 4-[[4-(2-Methyl-3-propan-2-yl-miso-4-yl) shout-2-yl]amino] hexanitro-p ratio The carboxylic acid ethyl ester 120858-90- 200811169 2-chloro-4-(2-methyl-3-propan-2-yl--oxazol-4-yl)-carcinine (Method 5; 70 mg' 0· 3 house Moer), 4-amino-1-hexahydro ρ ratio σ 缓 缓 乙 ( (1〇3 mg, 0.6 mmol), TEA (0.084 ml, 0.6 mmol) and ΙΡΑ (3 ml) They were combined and heated by microwave irradiation at 160 ° C for 5 hours. The solvent was evaporated; the residue was taken in DCM, washed with water, filtered over EtOAc The resulting material was purified by EtOAc EtOAc (EtOAc) NMR (400.132 MHz, CDC13) 1.20 (t,3H), 1.38 (m,2H), 1.49 (d,6H),1·99 (m,2H), 2.50 (s,3H), 2.91 (m,2H) ,3·91 (m,1H),4.07 (m,4H),4.89 (m,1H),5·51 (m,1H),6·68 (d,1H), 7.25 (s,1H), 8.14 (d,1H); MH+ 373· Example 65 Inward-8-methylmethyl-3_propanyl: carbazol-4-yl)pyrimidin-2-yl]·8-azabicyclo[3·2·1 ] oxa-3_amine is 2-bito-4-(2-methyl-3-propan-2-yl-miso-4-yl) bite (Method 5; 70 mg, 〇·3 mmol) ), inward-8-fluorenyl nitrogen bicyclo[3·2·1]oct-3-amine dihydrochloride (128 mg, 0.6 mmol), hydrazine (0·25 ml, 1.8 mmol) The mash (3 ml) was combined and heated at 160 ° C for 8 hours by microwave irradiation. The solvent was evaporated; the residue was dissolved in DCM and extracted with water. The aqueous phase was added to a SCX-3 column which had been previously wetted with MeOH. The column was rinsed with MeOH and the product was eluted with 2M ammonia in MeOH and eluent was evaporated. The title compound was purified by EtOAc EtOAc (EtOAc) NMR (400.132 MHz, CDC13) 1.46 (d,6H), 1.75 (m,2H), 1.87 (m5 2H), 2.08 (m,2H), 2.23 (m,5H),2·49 (s,3H), 3·13 (m, 2H), 4·05 (m, 1H), 5.33 (m, 1H), 5.64 (m, 1H), 6.67 (d, 1H), 7·26 (s, 120858 -91 - 200811169 1H), 8.11 (d, 1H); MH+ 341. Example 66 N-[l-(2-methoxyethyl) winter hexahydropyridyl]·4·(2-methyl-propan-2-yl oxazole • 4-yl)pyrimidin-2-amine 2-chloro-4-(2-methyl-3-propan-2-yl- oxazolyl)pyrimidine (Method 5; 70 mg '0.3 mmol) , u(2_methoxyethyl)hexahydropyridine_4_amine (95 mg, 〇·6 mmol), TEA (0.084 ml, 0.6 mmol) and IPA (3 ml) combined. And heated at 160 C for 5 hours by microwave irradiation. The solvent was evaporated; the residue was dissolved in DCM and washed with water, filtered th The resulting material was purified by a base-corrected ppjjpLC to give the title compound as a gum (34 mg, 32%). NMR (400.132 MHz, CDC13) 1.49 (d, 6H), 1.56 (m, 2H), 1·98 (m, 2H), 2.12 (m, 2H), 2.52 (m, 5H), 2.87 (m, 2H) , 3.29 (s, 3H), 3.45 (m, 2H), 3.77 (m, 1H), 4.90 (m, 1H), 5.56 (m, 1H), 6.65 (d, 1H), 7.24 (s, 1H), 8·12 (d,1H) ; MH+ 359· Example 67 Methyl-3-propan-2-yl-oxazol-4-yl)-N-(1-propyl-4-hexahydropyridinyl)---- 2-Amine 2-chloro-4-(2.methyl-3-propan-2-yloxazol-4-yl)&gt; Hydrazine (Method 5; 70 mg '〇·3 mmol), 1 -propyl hexahydropyridine 4-amine (85 mg, 0.6 mmol), TEA (0.084 mL, 〇·6 mmol) and ΙΡΑ (3 mL) combined, and under i6 (rc) The mixture was heated for 5 hours, the solvent was evaporated, and the residue was evaporated mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title compound was obtained as a title compound, which was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc Color solid (45 mg, 44%) NMR (400.132 MHz, CDC13) 0.84 (t, 3H), 1.47 (m, 10H), 2.01 (m, 4H), 2.23 (m, 2H), 2.50 (s, 3H) ), 2.82 (m, 2H), 3.76 (m, 1H), 4.90 (m, 1H), 5.58 (m, 1H), 6.65 (d, 1H), 7.24 (s, 1H), 8.12 (d, 1H) ; MH+ 343· Example 68 4-[2-[4_[[4·(2_methyl-3-propan-2-yl-miso-4-yl), dimethyl-2-yl]amino]-1 - hexanitrozide ratio biting base] thiol-ethyl] hexaploid bite _1_ retinoic acid third-butyl vinegar 4-(2-mercapto-3-propan-2-yl- miso-4_ ))-N-(4-hexahydropi-pyridyl) carcinoma π-t- 2-amine (Example 2, 100 mg, 0.33 mmol), 1-((1,1-didecylethoxy) Carbonyl)-4-hexahydroguanidine acetate (97 mg, 0.4 mmol), HATU (152 mg, 〇·4 mmol), DIPEA (0.23 ml, 1.33 mmol) and DMF (4 ml) Combine and stir at ambient temperature overnight. The solvent was evaporated, and the formed material was partitioned between DCM (2 mL) and sat. NaHC03 (2 mL). The resulting material was dissolved in DCM and purified on silica gel eluting with a shallow gradient of 〇 5% Me 〇 H / 〇 CM. The fractions containing the pure material were combined and evaporated to give the title compound (23 mg, 13%). NMR (400.132 MHz, CDC13) 1.07 (m, 2H), 1·37 (m, 11H), 1.49 (d, 6H), 1.68 (m, 2H), 1.94 (m, 1H), 2.05 (m, 2H) , 2.20 (m, 2H), 2_51 (s, 3H), 2.67 (m, 2H), 2.78 (m, 1H), 3·11 (m, 1H), 3·80 (m, 1H), 4.00 (m , 3H), 4.47 (m, 1H), 4·88 (m, 1H), 5.48 (m, 1H), 6.69 (d, 1H), 7.25 (s, 1H), 8.15 (d, 1H) ; MH+ 526 Examples 69-79 The following compounds were prepared by the procedure of Example 68 and using the appropriate acid starting materials of the same scale using 120858-93-200811169. Example compound NMR (400.132 MHz, CDC13) m/z 69 4-[3-[4-[[4-(2-methyl-3-prop-2-yl-) -2-yl]amino]-1-hexafluoropropanthyl]-3-S synthyl-propyl]hexahydromorphine-1-decanoic acid tert-butyl ester 1.37 (m, 11H), 1.49 (d, 6H), 2.05 (m, 2H), 2.37 (m, 4H), 2_48 (m, 5H), 2.67 (m, 2H), 2·78 (m, 1H), 3.12 (m, 1H), 3.36 (m,4H),3·80 (m,1H),3·98 (m,1H),4·44 (m, 1H),4·87 (m,1H),5·48 (m,1H) ), 6.69 (d,1H), 7.25 (s,1H),8·14 (d,1H) 541 70 4-[3-[4-[[4-(2-methyl-3-prop-2-) Ϋ-ϋ米嗤-4-yl) ornimidyl-2-yl]amino]-1-hexachloropyridyl]-3-keto-propyl]hexahydropyridine small carboxylic acid tert-butyl ester 1.05 (m, 2H), 1.38 (m, 12H), 1.52 (m5 8H), 1.61 (m, 2H) 5 2.05 (m, 2H), 2.30 (m, 2H), 2.51 (s, 3H), 2.61 (m, 2H), 2.78 (m, 1H), 3_11 (m, 1H), 3.78 (m, 1H), 4.00 (m, 3H), 4.45 (m, 1H), 4.98 (m, 1H), 5.49 ( m,1H),6.69 (d,1H), 7.26 (s,1H), 8.15 (d,1H) 540 71 4-methyl ice [4-[[4-(2-methyl-3-prop-2-) ·Base-mouth rice 嗤-4-yl) Pyridin-2-yl]amino] hexavalent batch -1-aminol] hexahydro outside 1: biting weiwei acid third-butyl ester 1.23 (s, 3H), 1.40 (m, 13H), 1.50 (d ,6H),2.06 (m,4H),2.51 (s, 3H), 2.96 (m,2H), 3.17 (m,2H), 3·58 (m,2H), 4.00 (m,1H), 4.26 ( m, 2H), 4·90 (m, 1H), 5.49 (m, 1H), 6.69 (d, 1H), 7·26 (s, 1H), 8.15 (d? 1H) 526 72 (3S)-3 -[2_[4-[[4-(2-methyl•3-propan-2-yl- ϋ米. sit-4_yl) 0 σ 定 -2--2-yl]amino] hexamethylene 0 ratio σ定基]-2-mercapto-ethyl]hexahydrate ρ σ 竣-1-decanoic acid tert-butyl ester U6 (m,1H),1·38 (m,12H), 1·49 (d ,6H), 1.56 (m,1H),1.82 (m,1H),2.06 (m,4H), 2.25 (m, 1H), 2.51 (s,3H), 2.63 (m,1H), 2.80 (m, 2H), 3.11 (m, 1H), 3.76 (m, 3H), 3.98 (m, 1H), 4.47 (m, 1H), 4.90 (m, 1H), 5.49 (m, 1H), 6·69 (d , 1H), 7.25 (s, 1H), 8.15 (d, 1H) 526 120858 94- 200811169 Example compound NMR (400.132 MHz, CDC13) m/z 73 (3R)-3-[2-[4-[[4 -(2-methyl-3-propan-2-yl-pyran-4-yl)pyrimidin-2-yl]amino] hexamethylene? σ 定 ] 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 ** 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 , 1.57 (m, 1H), 1.82 (m, 1H), 2.05 (m, 4H), 2.25 (m, 1H), 2.51 (s, 3H), 2.62 (m, 1H), 2.79 (m, 2H), 3.11 (m,1H), 3.76 (m,3H),3_98 (m5 1H), 4.47 (m5 1H), 4.89 (m,1H), 5.49 (m,1H), 6.69 (d,1H), 7.25 (s ,1H), 8.15 (d,1H) 526 74 2-Dimethylaminol-1-[4-[[4-(2-methyl-3-propan-2-yl)-m-but-4-yl) ♦ σ定-2-yl]amino]-1-hexafluoro-peptidyl] Ethyl ketone (DMSO) 1·37 (m, 2H), 1.50 (d, 6H)? 1.91 (m5 2H)5 2.20 ( S5 6H), 2·70 (m, 1H), 3·09 (m, 3H), 3.93 (m, 1H), 4.07 (m, 1H), 4.31 (m, 1H), 5·13 (m, 1H) ),6·80 (d,1H), 7·12 (broad s,1H), 7.35 (s,1H), 8.20 (d,1H) 386 75 3-diamylamino-1-[4-[[ 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]-1-hexahydrop-ratio sigma] propyl-1-b (DMSO) 1 · 49 (m, 2H), 1.50 (d, 6H), 1.81 (m, 2H), 2.44 (s, 3H), 2.63 (m, 1H), 2.72 (m, 1H), 2.83 (m, 1H), 3.11 (m5 1H), 3.92 (m, 2H), 4.33 (m, 1H), 5.62 (m, 1H), 6.81 (d, 1H), 7.16 (broad s, 1H), 7·37 (s, 1H), 8.21 (d,1H) 400 76 4-dimethylamino-1-[4-[[4-(2-methyl-3-propan-2-yl-isoxazole-4-yl)pyrimidin-2-yl] Amino]-1-hexahydrofolate b ϋ定基] Butan-1-one (DMSO) 1.39 (m, 2H), 1.51 (d, 6H), 1.84 (m, 2H), 1.93 (m, 2H) , 2.42 (m, 2H), 2.54 (s, 3H), 2.79 (s, 6H), 3_08 (m, 2H), 3.12 (m, 1H), 3.86 (m, 1H), 3·99 (m, 1H) ), 4·32 (m,1H), 5.62 (m,1H), 6.83 (d,1H), 7.23 (broad s,1H),7.51 (s,1H),8.27 (d,1H) 414 77 (1 -methyl-3-hexahydrop-rhenyl)-[4-[[4-(2-mercapto-3-propan-2-yl-ηm嗤-4-yl)) Amino] hexahydroadenine 匕 定 ] ] ] 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣 嗣, 2.58 (s, 3H), 2.87 (m, 4H), 3.20 (m, 1H), 3.95 (m, 1H), 4.07 (m, 1H), 4.52 (m, 1H), 4.96 (m, 1H) ), 5.57 (m, 1H), 6.77 (d, 1H), 7.31 (s, 1H), 8·21 (s, 1H) 426 120858 -95- 200811169 Example compound NMR (400.1 32 MHz, CDC13) m/z 78 [4-[[4-(2-mercapto-3-propan-2-yl-imidazolidyl)pyrimidin-2-yl]amino] hexahydroindole fluorenyl Hi- Methyltetrahydropyrrol-2-yl)methanone 1.43 (m5 2H), 1.55 (d, 6 Η) 5 1·62 (m, 2H), L86 (m, 4H), 2.10 (m, 2H), 2.22 ( m,1H), 2.38 (s,3H), 2.56 (s,3H),2·86 (m,1H),3.08 (m,1H),3.15 (m,2H), 4.11 (m, 2H),4.54 (m,1H), 4.97 (m,1H), 5·57 (m,1H),6.77 (d,1H),7.32 (s,1H),8.21 (d,1H) 412 79 2-[4-[ [4-(2-methyl-3-propan-2-yl]m β-tetra-4-yl)N-pyridyl-2-yl]amino]hexahydropyridinium carbonyl] morphine carboxylic acid The third-butyl ester 1.45 (s, 9H) overlaps 1.45 (m, 2H), 1·54 (d, 6H), 2·12 (m, 2H), 2.57 (s, 3H), 3.00 (m, 1H) , 3.18 (m, 2H), 3.53 (m, 2H), 3.90 (m, 2H), 4.07 (m, 2H), 4.48 (m, 1H), 4.96 (m, 1H), 5.55 (m, 1H), 6.76 (d, 1H), 7_31 (s, 1H), 8.20 (d, 1H) 514 Example 80 1·[4_[[4-(2•methyl_3-prop-2-yl-imidazol-4-yl) ) 痛 _2 _ _ _ 】 】 】 】 】 】 】 -2- -2- -2- -2- -2- -2- -2- -2- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4-(2-Methyl-3-propan-2-yloxazol-4-yl).密-2-yl]amino] hexahydropyridyl]-2-keto-ethyl]hexahydropyridine small carboxylic acid third _ butyl g (example 68, ~170 mg, 0.33 mmol) Dissolve in DCm (3 mL) and add an equal volume of TFA. The reaction was stirred at ambient temperature for 3 hours and then added to a 5 g SCX-3 column pre-wetted with MeOH (2 column volumes). The column was dissolved in MeOH (2 column volumes) and the product was eluted with 2M ammonia in Me. The basic eliminator was evaporated to give the title compound as a glassy material (46 mg, 27%). NMR (500.133 MHz) 1.10 (m5 2H), 1.44 (m, 2H), 1·51 (d, 6H), 1·62 (m, 2H), L81 (m, 1H), 1.93 (m, 2H), 2.22 (m,2H), 2.47 (s,3H),3·99 (m,1H),4·10 (m,1H),5·58 (m,1H),6·62 (d,1H), 6·76 (d, 1H), 7.28 (s, 1H), 8.19 (d, 1H); MH+ 426. 120858-96 - 200811169 Examples 81-85 The compound of the formula is by the procedure of Example 8 and is the same Made under the scale. Appreciable compound i/g ~α 4曰1 NMR (500.133 MHz) mouth j chim m/z SM a 81 H4-[[4-(2-methyl-propan-2-yl-mouth σ sit-4- Aminopyrimidin-2-yl]amino]sodium hexahydro outside I: octyl]-3-hexahydro ρ than ploughed small base-propion-Ι-g with 1.46 (m, 2H), 1.51 (d, 6H) , 1.93 (m, 2H), 2.33 (m, 4H), 2.47 (m, 5H), 2.55 (m, 2H), 2.70 (m, 4H), 3.98 (m5 1H), 4_09 (m, 1H), 5.58 (m,1H), 6.62 (d,1H), 6.76 (d, 1H), 7.28 (s,1H), 8.19 (d,1H) 441 Example 69 82 1 -[4-[[4-(2- Benzyl-3-propan-2-yl-^-m--4-yl)pyrimidin-2-yl]amino]-1-hexa- sinus chinyl]-3-(4-six-rat ratio 17 base) C-U is the same as 1.03 (m, 2H), 1.35 (m, 1H), 1.47 (m, 4H), 1.51 (d, 6H), 1.61 (m, 2H), 1.93 (m, 2H), 2.31 (m, 2H), 2·47 (s, 3H), 3.98 (m, 1H), 4.09 (m, 1H), 5.58 (m, 1H), 6.62 (d, 1H), 6.76 (d, 1H), 7.28 (s , 1H), 8.19 (d, 1H) 440 Example 70 83 (4-mercapto-4-hexamethyl p-pyridyl H4-[[4-(2-methyl-3-prop-2-yl-mouth) 〇-4-yl) ° σ 定 _2 2 -yl]amino]-1-hexahydropyridinyl] ketone 1.29 (s, 3H), 1.47 (m, 2H), 1.50 (d,6H), 1.65 (m, 2H), 1.96 (m, 2H), 2.21 (m, 2H), 2.47 (s, 3H), 3.00 (m, 4H), 3.15 (m, 2H) ), 4.02 (m, 1H), 4.19 (m5 2H)? 5.54 (m5 1H), 6.76 (d, 1H), 7.28 (s, 1H), 8.19 (d, 1H) 426 Example 71 120858 97- 200811169 Example compound NMR (500.133 MHz) m/z SM 84 H4-[[4-(2-methyl-3-propan-2-yl·.mysin-4-yl)pyrimidin-2-yl]amino hexammine Base]_2-[(3S)hexahydropyridyl]ethanone 1.25 (m,1H), 1.46 (m, 2H), 1·50 (d,6H),1·66 (m,1Η), 1.80 ( m,2Η), 1.94 (m,2H), 2.19 (m, 1H), 2.33 (m,2H), 2.47 (s,3H), 2.61 (m,1H), 2·76 (m,1H), 3.19 (m, 1H), 3·27 (m, 1H), 3·99 (m, 1H), 4.09 (m, 1H), 5.55 (m, 1H), 6.77 (d, 1H), 7·28 (s , 1H), 8.19 (d, 1H) 426 Example 72 85 1·[4-[[4-(2-Mercapto-3-propan-2-ylmist-4-yl)-N-n-but-2-yl Amino]-1-hexahydrogen 1: sigma]-2-[(3R)-3-hexahydropyridyl]ethanone 1.25 (m,1H),1·46 (m, 2H), 1.50 ( d,6H),1.66 (m,1H), 1.80 (m,2H), 1.94 (m,2H),2·19 (m, 1H),2·33 (m , 2H), 2·47 (s, 3H), 2.62 (m, 1H), 2.77 (m, 1H), 3.19 (m, 1H), 3.28 (m, 1H), 3.99 (m, 1H), 4.09 ( m,1H), 5.55 (m,1H), 6.77 (d, 1H), 7.28 (s,1H), 8.19 (d,1H) 426 Example 73 Example 86 [4_[[4-(2_methyl-3) -propan-2-yl-oxazol-4-yl)-hydan-2-yl]amino]-1_hexa-hydropyridyl]-floryl V-lin-2-yl-carboxamidine in dioxane 4M HC1 (4 ml) was added to 2-[4-[[4·(2-methyl-3-propan-2-yl-imidazol-4-yl)piperidin-2-yl]amino]hexahydro Pyridine_1-carbonyl]fosfolin-4 was acidified in a solution of the third-butyl ester (Example 79; 〇·3 g, 0.58 mmol) in DCM (4 mL). After stirring for 16 hours, 2 NaOH was added to adjust to pH 12 and the aqueous layer was extracted with DCM (3 X 15 mL). The combined organic material was dried under reduced pressure, filtered, and concentrated in vacuo to give a colourless foam. The title compound was obtained as a colorless foam (19·················· NMR (CDC135 400.132 MHz) 1.46 (m5 2H)5 1.56 (d, 6H)5 2.12 (m5 2H), 2.57 (s5 3H), 2.89 (m, 3H), 3.20 (m, 2H), 3.67 (m, 1H) ), 3.84 (m, 1H), 4.04 (m5 2H), 4.21 (m5 1H), 4_47 (m, 1H), 4.98 (m, 1H), 5.53 (m, 1H), 6.74 (d, 1H), 7.31 (s, 1H), 8.21 (d, 1H); MH+ 414· Example 87 3·[[4_(2-methyl-3-prop-2-ylpyran-4-yl), bit-2-yl] Amino] tetrahydro-p-bi-l-carboxylic acid tert-butyl ester _methylamino-1-(2-indolyl-3·propan-2-yl-miso- ol-4-yl) propyl-1 - Ketone (Method 24, WO 03/076436, 1.85 g, 8.36 mmol), 3-Aminocarbinimidium tetrahydropyrrolecarboxylic acid tert-butyl ester (Method 2; 2.1 g, 9_1 m Mol) and 2-methoxyethanol (2 mL) were combined and heated under reflux for 24 hours. The reaction mixture was allowed to cool to ambient temperature and evaporated to give a yellow viscous gum. Add ether (~1 〇〇 ml) and allow the mixture to oscillate with sonication. The solid precipitate was collected by suction filtration, and dried under vacuum to give the title compound, which was evaporated to dryness (yel. The solid precipitate was collected by suction filtration and dried in vacuo to give the title compound as a white solid, which was purified on a silica gel (12 g cartridge) by flash chromatography. 10% =0 Η dissolution. The product-containing fractions were combined and evaporated to give a crystallite. Ying Han (4(10) 1·4〇(m, 9HX 1.49 (d5 6H)5 1.91 (m5 1H)5 2.11 (m5 1H)5 2.48 (s, 3H)5 3.19 1H)5 3.45 (m5 IK), 3.55 (m5 1HX 4.32 (m, 1H)5 5.69 (m3 1H)5 6.86 (d5 120858 -99- 200811169 1H), 7.35-7.43 (m, 2H), 8.23 (d, 1H) ; MH+ 387.3. Example 88 4-(2 -Methyl-3-propan-2-yl-miso-4-yl)-N-tetrahydroppylo-3-yl-t-bit-2-amine gives 3-[[4·(2-methyl) -3_propan-2-yl-imidazole·4-yl)- phen-2-yl]amino]tetrahydro-p-pyrrolic acid carboxylic acid tert-butyl ester (Example 87; 855 mg, 2.21 mmol) Dissolved in DCM (10 mL), EtOAc (EtOAc)EtOAc. Wash with MeOH (100 mL). Dissolve the product from the cartridge with 2M ammonia (100 mL) in Me. H. Evaporate the basic solvent to give amber gum (~500 mg). Purification by chromatography, eluting with a gradient of 0-15% of 2M ammonia/MeOH in DCM. Evaporation of the fractions containing the product to give a yellow gum which was developed in ether/sound and was gray The title compound was obtained as a white solid (yield: 230 mg, 36%). NMR (400.132 MHz) 1.49 (d, 6H), 1.66 (m, 1H), 2.02 (s, 1H), 2.48 (s, 3H), 2.74 (m5 2H), 2.94 (m, 2H), 4.25 (m, 1H), 5.68 (m, 1H), 6.80 (d, 1H), 7.11 (brs , 1H), 7.35 (s, 1H), 8.20 (d, 1H); MH+ 287.4. Example 89 4-(2-methyl-3-propan-2-yl-imidazole-4-yl)-N-(l - mercaptosulfonyltetrahydropyrrole)pyrimidine-2-amine Addition of catalyst DMAP (5 mg) to DIPEA (0.07 mL, 0,42 mmol) to 4-(2-mercapto-3- Prop-2-yl-ηm-sial-4-yl)·Ν·® hydrogen p pirin-3-yl "Bite-2-amine (Example 88; 62 mg, 0·22 mmol) in DCM ( 2 ml) was stirred in the solution. Then, gasified decanesulfonium (0.025 ml, 〇·32 mmol), 120858-100-200811169 was added and the reaction mixture was stirred at ambient temperature for 16 hours. Additional DCM (20 mL) and water (15 mL) were then added and the mixture was shaken and then poured over a phase separation cartridge. The organic dissolving agent was evaporated to dryness to give a pale yellow gum which was combined with water and concentrated in vacuo. The obtained yellow gum was dissolved in DCM (15 mL), EtOAc (EtOAc m. The residue was triturated with EtOAc (EtOAc)EtOAc. NMR (400.132 MHz) 1.55 (d,6H),2·04 (m,1H), 2.26 (m,1H),2·54 (s,3H), 2.95 (s,3H),3·25 (m, 1H), 3.49-3.62 (m, 3H), 4·46 (m, 1H), 5.69 (m, 1H), 6.93 (d, 1H), 7_41-7_49 (m, 2H), 8.31 (d, 1H); MH+ 365.3. Example 90 3-[[4_(2·Indolyl-3·propan-2-yl-carzol-4-yl)-oxin-2-yl]amino]tetrahydropyrrole Amine at 130 C, 4-(2-methyl-3-propan-2-yl-isosphen-4-yl)-indole-tetrahydro-external b σ--3-yl^-mididine-2-amine (Example 88; 62 mg, 〇22 mol) and a solution of sulfonamide (102 mg '1.06 mmol) in ι,4-dioxane (2 mL), heated by microwave irradiation 30 minute. The reaction mixture was evaporated, and a saturated aqueous NaHCO? The aqueous layer was extracted with DCM (2×10 mL). The combined organic material was washed with brine, dried over magnesium sulfate, filtered and evaporated. Purification by flash chromatography on EtOAc (EtOAc) elute NMR (400.132 MHz) 1.50 (d,6H), 1.94 (m5 1H), 2.18 120858 -101 - 200811169 (m,1H), 2.48 (s,3H),3.04 (m,1Η),3·19 (m, 1Η),3·33 (m,1H), 3.46 (m, 1H), 4.39 (m,1H),5·65 (m,1H), 6.75 (s,2H), 6.86 (d,1H), 7.29 -7.38 (br m,1H), 7.37 (s,1H),8·24 (d,1H) ; MH+ 366.2. Example 91 l-[3-[[4_(2_methyl_3_丙_2_) Base-methazole-4_yl)acridine·2_yl]amino]tetrahydropyrrole-1-yl]acetamidine acetic anhydride (0.060 ml, 〇·64 mmol) is added dropwise to 4_(2 _Methyl_3_ propyl_2_yl·Miso _4_yl) Tetrahydro-p-Bilo-3H-But-2-amine (Example 88; 100 mg, 0.35 mmol) with tea (0.10 mL, 〇_ 72 mmoles in a solution in DCM (3 mL). The reaction mixture was stirred for 2 h then water (5 mL) and DCM (5 mL). The mixture was filtered through a pad of <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The gum was triturated with EtOAc (EtOAc)EtOAc. NMR (400.132 MHz) (rotational isomer) 149 fine, 6H), 188 2 〇3 (m, 4H), 2 〇5_ 2·24 (m, 1H), 2·48 (m, 3H), 3.43 ( m,2H),3·56_3·75 (m,2H),4·31_4·44 (m, 1H), 5.66 (m,1H), 6.86 (m,1H),7.34-7.49 (m,2H), 8·24 (m,1H) ; MH+ 329.3. Example 92 N-[l-(3-Actylpropylsulfonyl)tetrahydropyrrole_3•yl]methylpropanyl-imidazole-4_yl Pyrimidine-2-amine 裇 compound by the procedure of Example 3 and using 4·(2-methyl-3-propan-2-yl-isoxazole)-N_tetrahydropyrrole at the same scale 3_Base-Nipyl-2-amine (Example S8) was prepared as a starting material. Nmr (4〇〇I% I.%), 2% 120858 -102- 200811169 (m5 1H)? 2.18 (m5 2H)5 2.28 1H)5 2.54 (s5 3H)5 3.25-3.45 (m5 4H)5 3,56 (m5 1H)5 3.65 (m5 1H)5 3.79 (t5 2H)5 4.47 (m5 1H)5 5.69 (m, 1H)3 6.93 (d5 1H),7·42 (s,1H),7· 48 (m, 1H), 8% (Shan Qiu; € Example 93-98 The following compounds were prepared by wall LA Jingtian only Example 68, and using 4-(2-methyl-3-propyl) at the same scale -2-yl-peri #木1 4 base)-Ν-tetrahydro ρ, bilo-3-yl-π-deni-2-amine (Example 88), suitable acid starting material &lt; 〇 Example ------- Compound ^η 巧0 NMR (500. 133 MHz) m/z 93 4-〇[3-74-(2-methyl-4-propan-2-ylimidazolium-4-yl)-dithio-2-yl]amino]tetrahydrophyllin-1 _yl]-2-keto-ethyl]hexahydropyridine-1 acid-containing ^ Third-butyl ester (373K) 1. 09 (m, 2H), 1. 40 (s, 9H), 1. 51 (d, 6H), 1. 67 (m, 2H), 1. 87-2-06 (m5 2H), 2· 17 (m, 3H), 2·49 (s, 3H), 2. 74 (m, 2H), 3. 28-3. 77 (m, 4H), 3. 88 (m, 2H), 4. 43 (m, 1H), 5. 58 (m, 1H), 6. 82 (d, 1H), 6. 94 (m, 1H)? 7. 33 (s, 1H) 3 8. 23 (d? 1H) 512. 4 94 4-[3-[3-[[4-(2_ 曱-propenyl-2-yl)---------]-]-] 1-yl]-3-yl-endo group] hexahydropyrrol-1-carboxylic acid tert-butyl ester (373K) 1. 41 (s, 9H), 1. 50 (d, 6H), 1. 89-2. 26 (m, 2H), 2. 32-2. 43 (m, 6H), 2. 47 (s, 3H), 2. 61 (m, 2H), 3. 25-3. 83 (m, 8H), 4. 43 (m, 1H), 5·58 (m, 1H), 6. 81 (d, 1H), 6. 91 (s, 1H), 7. 29 (s, 1H), 8. 22 (d, 1H) 527. 3 95 4-[3-[3-[[4-(2•methylpropan-2-yl-isosyl-4-yl]&gt; dimethyl-2-yl]amino]tetrahydroanthracene 17 Tri-butyl ketone (373K) of each -1-yl]-3-keto-diyl]hexahydropyridine-1-carboxylic acid 01 (m, 2H), 1. 40 (s, 9H), 1. 42-1. 54 (m, 9H), 1. 63 (m, 2H), 1. 89-2. 28 (m, 4H), 2. 48 (s, 3H), 2. 70 (m, 2H), 3. 27-3. 73 (m, 4H), 3. 89 (m, 2H), 4. 43 (m, 1H), 5·58 (m, 1H), 6. 81 (d, 1H), 6. 93 (m, 1H), 7. 32 (s, 1H), 8. 23 (d, 1H) 526. 4 120858 -103- 200811169 Examples Compound NMR (500. 133 MHz) m/z 96 4-methyl-4-[3-[[4-(2-methyl-3-propan-2-ylaminoindole-4-yl)pyrimidin-2-yl]amino]tetra Hydropyrrole small carbonyl]hexahydropyridine small carboxylic acid third-butyl ester (373K) 1. 18 (s,3H),1·36 (m, 2H),1·40 (s,9H),1·51 (d,6H), 1. 94 (m, 1Η), 2·06 (m, 2Η), 2. 15 (m, 1H), 2_49 (s, 3H), 3. 15 (m, 2H), 3. 44-3. 58 (m, 4H), 3. 69-3. 82 (m, 2H), 4. 41 (m, 1H), 5. 57 (m, 1H), 6. 82 (d, 1H), 6_93 (m, 1H), 7·33 (s, 1H), 8. 23 (d, 1H) 512. 6 97 (3R)-3-[2-l&gt;[[4-(2-methyl-3-propan-2-yl-sodium-sodium-4-yl))-yl-2-yl]amino] Tetrazolium p-l-l-yl]-2-mercapto-ethyl]-six-p-pyr-pyrene-1-butylic acid tert-butyl ester 1. 21 (m, 1H), 1. 32-1. 43 (m, ), 1. 51 (d, 6H), 1.57 (m, 1H), 1. 78 (m, 1H), 1. 84-2. 29 (m, 5H), 2·48 (s, 3H), 2. 67 (m, 1H), 2. 85 (m, 1H), 3. 27-3. 83 (m, 6H), 4. 43 (m, 1H), 5. 58 (m, 1H), 6. 81 (d, 1H), 6. 94 (m, 1H), 7. 32 (s, 1H), 8. 23 (d, 1H) 512. 6 98 (3S)-3-[2-[3-[[4-(2-methyl-3-propan-2-yl--suppur-4-yl)).密口定-2-yl]amino]tetrazolium-l-yl]-2-methylidyl-ethyl]hexa-pyrene-pyrene-1-butylic acid tert-butyl ester (373K) 21 (m, 1H), 1. 33-1. 43 (m, 10H), 1. 51 (d, 6H), 1. 57 (m, 1H), 1. 78 (m, 1H), 1. 84-2. 29 (m, 5H), 2. 49 (s, 3H), 2. 67 (m5 1H), 2. 85 (m, 1H), 3. 28-3. 83 (m5 6H), 4. 43 (m, 1H), 5. 58 (m, 1H), 6. 82 (d, 1H), 6. 94 (m, 1H), 7. 33 (s, 1H), 8. 23 (d, 1H) 512. 6 Examples 99-104 The following compounds were subjected to the procedure of Example 80 and replaced with 4-[2-[4-[[4-(2-methyl-3-propyl-)- 2-based-miso 唆4_yl) ππ定-2-yl]amino]-1-hexahydro ton σ-decyl]-2-S-iso-ethyl]hexahydrop ratio bite_ι_魏Made from acid tert-butyl ester (Example 68). 120858 104- 200811169 Examples Compound NMR (500. 133 MHz) m/z SM 99 H3-[[4-(2-methyl-3-propan-2-yl-flavor. sit-4-yl)pyrimidin-2-yl]amino]tetrahydropyrrol _1_基]-2_(4-hexahydroexyridinyl)ethanone (500. 133 MHz) 0. 95-1. 10 (m, 2H), 1·47 (m, 6H), 1·58 (m, 2Η), 1·76 (m, 1Η), 1. 87-2. 00 (m5 1Η), 2. 04-2. 21 (m, 3H) 5 2. 38-2. 48 (m5 5H) 5 2. 87 (m, 2H), 3. 34-3. 53 (m, 4H), 4. 26-4. 42 (m, 1H), 5. 65 (m, 1H), 6. 84 (m, 1H), 7. 30-7. 49 (m, 2H), 8. 22 (m? 1H) 412. 3 Example 93 100 Η3-[[4·(2-methyl-3-propan-2-yl-flavor-4-yl)-only. _2_2_yl]amino]tetrahydropyrrolidyl]-3-hexahydropyrrol-1-yl-propion-Ι-g 48 (m, 6H), 1. 87-2. 01 (m, 1H), 2. 02-2. 22 (m, 1H), 2. 22-2. 40 (m, 6H), 2. 44-2. 52 (m, 5H), 2. 63 (m, 2H), 2. 67 (m, 2H), 3. 24-3. 70 (m, 4H), 4. 27-4. 43 (m, 1H), 5. 65 (m, 1H), 6. 84 (m, 1H), 7. 31-7. 49 (m, 2H), 8. 22 (m, 1H) 427. 2 Example 94 101 1-[3-[[4-(2-methyl-3-propan-2-ylamino-4-yl)pyrimidin-2-yl]amino]tetrahydropyran-1-yl ]-3-(4-hexahydropurine 匕 定 )) propan-1-one 0. 97 (m5 2H)5 1. 24-1. 33 (m, 1H), 1. 35-1. 61 (m, 10H), 1. 87-2. 24 (m, 4H), 2·34_2·47 (m, 5H), 2. 89 (m, 2H), 3. 22-3. 73 (m, 4H), 4. 26_4_43 (m, 1H), 5. 65 (m, 1H), 6. 84 (m, 1H), 7. 31-7. 48 (m, 2H), 8. 22 (m, 1H) 426. 3 Example 95 102 (4-methyl-Hyperhydropyridinyl)-[3-[[4-(2-methyl-3-propan-2-yl-m-oxazol-4-yl)pyrimidine-2 -yl]amino]tetrahydropyrrol-1-yl]methanone (373K) 1. 15 (s5 3H)? 1. 35 (m, 2H), 1. 50 (m, 6H), 1. 93 (m, 1H), 2. 02 (m, 2H), 2. 15 (m, 1H), 2. 47 (s, 3H), 2. 64-2. 78 (m, 4H), 3. 46-3. 56 (m, 2H), 3. 72 (m, 1H), 3. 80 (m, 1H), 4. 39 (m, 1H), 5. 58 (m, 1H), 6. 81 (d, 1H), 6. 88 (m, 1H), 7·29 (s, 1H), 8. 22 (d, 1H) 412. 4 Example 96 120858 • 105 - 200811169 Example Compound NMR (500. 133 MHz) m/z SM 103 1-[3-[[4-(2-methyl-3-propan-2-yl-miso-4-yl)p-deni-2-yl]amino]tetra Hydropyrrolidin-1-yl]-2-[(3S)-3-hexahydropyridinyl]ethanone 1. 04 (m, 1H), L33 (m, 1H), 1·44_1·55 (m, 7H), 1. 66-2. 22 (m, 7H), 2. 40 (m, 1H), 2·46 (s, 3H), 2. 78-2. 94 (m3 2H) 5 3. 25-3. 54 (m, 4H), 4·27-4_43 (m, 1H), 5. 65 (m, 1H), 6. 84 (m, 1H), 7. 33-7. 49 (m, 2H), 8. 22 (m, 1H) 412. 4 Example 97 104 H3-[[4-(2-Methyl-Hexyl-2-yl-indolyl)--4-yl)pyrimidin-2-yl]amino]tetrahydropyrrole-1-yl]-2- [(3R)-3-hexahydropyridinyl]ethanone 1. 04 (m, 1H), 1. 33 (m, 1H), 1. 44-1. 55 (m, 7H), 1. 66-2. 11 (m, 7H), 2. 39 (m5 1H), 2_46 (s, 3H), 2·77_2·93 (m, 2H), 3. 23-3. 73 (m5 4H), 4. 26-4. 43 (m5 1H) 5 5. 65 (m, 1H), 6. 84 (m, 1H), 7. 32-7. 48 (m, 2H), 8. 22 (m, 1H) 412. 4 Example 98 Example 105 4-(2-Methyl-propan-2-yl-2-oxazol-4-yl)-Ν·[1-(3-tetrahydropyrrole-1-propylsulfonyl)tetrahydropyridinium洛-3_基】Urine bite-2_amine will be added to the 4-(2·A) by 3-chloro-1-propyl chlorination (〇·〇46 ml, 〇·38 mmol) 3-Benzyl-2-yl-imidazol-4-yl)-indole-tetrahydropyrrol-3-ylminopyridine-2-amine (Example 88; 73 mg, 〇 25 mmol) with TEA (0 . 070 ml, 〇·5 〇 millimolar in a solution in DCM (2 ml). The reaction mixture was stirred for 3 hrs then water (5 mL) and DCM (5 mL). The organic layer was separated, followed by evaporation to give an off-white solid, which was dissolved in EtOAc (3 liters), then sodium iodide (5 mg, 〇·〇 3 mM) and tetrahydropyrrole (〇·1 〇 ml) ,1. 20 millimoles). The reaction mixture was heated with mp EtOAc (EtOAc) (EtOAc) NMR (400. 132 MHz, CDC13) 1. 56 (d, 6H), 1. 85 (m, 4H), 2. 00-2. 15 (m, 3H), 2. 32 (m, 1H), 2. 58 (s, 3H), 2. 64-2. 78 (m, 6H), 3_11 (m, 2H), 3. 36 (m, 1H), 3. 55 (m, 2H), 3. 72 (m, 1H), 4. 56 (m, 1H), 5. 58 (m,1H),5·68_5·93 (m,1H),6·79 (d,1H),7. 34 (s, 1H), 8. 19 (d,1H) ; MH+ 462·3· Example 106 4_(2-M-propyl-propyl- oxazolamide) good [l-[3-(4·propyl-2-ylhexanitropyrazine-1- Propyl) propyl hydrazino] tetrahydroindol-3-yl] ace-2-amine with sodium iodide (5 mg, 〇·〇 3 mmol) and 1-isopropyl hexahydropyrazole ( 116 mg '〇·90 mmol> added to ΝΚ3·chloropropylsulfonyl)tetrahydropyrroleyl]·4_(2-methyl-3-propan-2-yl-imidazolidyl) -2-amine (Example 92; 75 mg, 0. 18 Torr in a solution in THF (3 mL). The reaction mixture was heated by microwave for 45 minutes at 15 cc. The reaction mixture was cooled with EtOAc EtOAc m. NMR (400·132 mHz, CDC13) 1. 33 (d,6H), 1·59 (t,6H),2·05 (m,3H),2·35 (m,1H),2·61 (t,2H), 2. 65 (s, 3H), 2·79-2_97 (m, 8H), 3Ό7 (m5 2H), 3. 4G (m, 2H), 3. 56 (m, 2H), 3. 72 (m,1H), 4·58 (m,1H),5·57 (m,1H),5. 78 (m, 1H), 6. 83 (d, 1H), 7. 43 (s, 1H), 8. 25 (d, 1H) ; MH+ 519. 3.  Examples 107-108 The following compounds were prepared by the procedure of Example 106 and using the appropriate amines on the same scale. 120858 -107- 200811169 Example Compound NMR (400. 132 MHz, CDC13) m/z 107 N-|&gt;[3-(2-methoxyethylamino)propylsulfonyl]tetrazine p-bi-3-yl]-4-(2-oxime Alkyl-3-propan-2-yl-isoxazole_4_yl)pyrimidin-2-amine 1·56 (d,6H), 2. 08-2. 37 (m, 4H), 2. 58 (s, 3H), 3. 03 (m, 4H), 3-11-3. 72 (m, 8H), 3·37 (s, 3H), 4. 54 (m, 1H), 5. 59 (m, 1H), 6. 08 (m, 1H), 6. 80 (d, 1H) 5 7. 36 (s5 1H)5 8. 19 (d5 1H) 466. 3 108 N-j&gt;[3-(4_f hexahydro^~h_1_yl)propyl]]tetrahydropyrrol-3-yl]-4-(2-methyl-3-propan-2 -基-嗤嗤_4_基) 咬_2_amine 1. 56 (d, 6H), 2. 02 (m, 3H), 2·32 (m, 1H), 2·39 (s, 3H), 2. 50 (t, 2H), 2. 53-2. 69 (m, 11H), 3. 07 (m, 2H), 3. 35 (m,1H), 3·55 (m,2H), 3·72 (m,1H), 4. 56 (m, 1H), 5·58 (m, 1H), 5. 72 (m, 1H), 6. 80 (d, 1H), 7. 35 (s, 1H), 8. 19 (d, 1H) 491. 3 Example 109 N_methyl_3-[[4-(2-methyl_3_propan-2-yl-oxazol-4-yl)-anthran-2-yl]amino]tetrahydropyrrole carboxy Indoleamine 4-(2-methyl-3-propan-2-yl-m-[pi]-4-yl)-N-tetrahydrop-pyr- 3-yl" dimethyl-2-amine (Example 88; 144 mg, 〇_5 mmol, dissolved in methyl isocyanate (1 〇 5 mg) in THF (2 mL) and stirred at ambient temperature for 2 hr. 2 〇〇 mg), the reaction mixture was gently stirred for 3 〇, then filtered, and evaporated in vacuo to give a colorless gum. Add DCM (0. The title compound was obtained as a colorless foam (51 mg, 3% NMR (CDCl3) 15i (d, 6H), 1. 95-2. 05 (m, 1H), 2. 13-2. 24 (m, 1H), 2. 58 (s, 3H), 2. 74 (s, 3H), 3. 37-3. 42 (m, 2H) 5 3. 47-3. 61 (m, 2H), 5. 47-5. 66 (m, 1H)? 6. 73 (d3 1H) 5 7. 43 (s, 1H), 8. 04 (d, 1H).  Example 110 N-(2-dimethylaminoethyl) each [[4-(2-methylisopropionyl-imidazolidinyl)pyrimidine_2_ 120858 -108- 200811169 yl]amino]tetrahydrofur -i_Tremine heading compound was used in a similar manner to Example 22, and using 4-(2-methyl-3-propan-2-yl-m-m-[beta]-4-yl)-N- at a similar scale The concave hydrogen ρ is inferior to the indole-3-yl-σ-spottle-2-amine (Example 88) instead of 4-(2-methyl-3-propan-2-yl-flavor _4_yl)_Ν_(4-six Hydrogen ρ ratio. Alkyl pyrimidine (Example 2), prepared with the appropriate amine. NMR (CDC13, 400 MHz) 1·56 (d, 6H), 1. 95-2. 07 (m, 1H), 2. 19-2. 32 (m, 7H), 2. 43 (t, 2H), 2. 57 (s, 3H), 3·28-3·41 (m, 3H), 3. 43-3. 60 (m, 2H), 3·66-3·76 (m, 1H), 4. 49-4. 60 (m, 1H), 4. 89 (s, 1H), 5. 15 (d, 1H), 5. 52-5. 67 (m, 1H), 6_78 (d, 1H), 7. 32 (s5 1H), 8. 21 (d5 1H) ; MH+ 401. 6.  Example 111 (3S)-3-[[4-(2-indolyl-3-propan-2-yl]-oxazol-4-yl)cyclopyridine-2-yl]amino]hexahydropyridine small carboxylic acid Tri-butyl ester 2-chloro-4-(2-mercapto-3-propan-2-yl)methane-4-yl) oxime (Method 5; 5. 0 grams, 21. 2 millimolar), tea (6.5 ml, 46·6 mmol) and (3S)-3_aminopiperidine small carboxylic acid tert-butyl ester (4·33 g, 14. 2 millimoles) was added to DMA (100 liters) and heated at ll 〇 °C for 16 hours. The solvent was evaporated to give a yellow gum, &lt;RTI ID=0.0&gt;&gt; The combined organic materials were dehydrated and dried, and the solvent was removed in vacuo to give a dark gum (7 gram). MH+ 4〇1.  Example 112 4_(2_methyl_3_propan-2-yl·^, salivyl) with [(4) each hexanitrozide group] Cyclopyridylamine (3S)_3-[[4-(2_ Methyl _3_propan-2-yl benzoxazole hydrazin-2-yl]amino]hexafluoropyridinium 1-carboxylic acid second-butyl ester (example ^; 5 · 5 g, ΐ 2 · 9 毫Mol) is dissolved in B (30 pens), and added 6 hC1 (5 〇 ml) in propanol. The reactants (4) for 120 hrs - 109 · 200811169 are then evaporated to dryness to obtain The gum was dissolved in water (100 ml), and solid NaHC〇3 was added, and the mixture was taken to be alkaline. The aqueous layer was extracted with DCM (3×200 mL), dried and dried, and solvent was removed in vacuo. The title compound was obtained as a dark gum (2.). 5 grams). NMR (400. 132 MHz, CDCl3) (m, 8H), 1 74 1 82 (4) 1H), 1. 92-2. 00 (m, 1H), 2. 56 (s, 3H), 2. 68 (dd, 1H), 2. 72-2. 78 (m, 1H), 2. 87-2. 92 (m, 1H), 3. 18-3. 22 (m, 1H), 3. 93-3. 96 (m, 1H), 5_39 (d, 1H), 5. 55-5. 67 (m, 1H), 6. 71 (d, 1H), 7. 30 (s, 1H), 8. 19 (d,1H) ; MH+ 301· Example 113 (3R)-3-[[4-(2.methyl-3-propan-2-yl- oxazol-4-yl)----- Amino]hexahydropyridinium small acid-reducing third-butane vinegar title compound is similar to the example ill and uses (3R)-3-aminopiperidine-1-carboxylic acid third at a similar scale - Butyl ester is prepared as a starting material. MH+ 401.  Example 114 4-(2-Methyl-3-propan-2-yl-oxazolyl)-N-[(3R)-3-hexahydropyridyl]-pyridin-2-amine The title compound was similar to Example 112 Mode, and using (3R)-3_[[4-(2-methyl-3·propan-2-yl-imidazol-4-yl)-anthran-2-yl]amino]hexahydropyridine on a similar scale 1-carboxylic acid tert-butyl ester (Example 113) was prepared as a starting material. NMR (400. 132 MHz, CDC13) 1. 51-1. 57 (m, 6H), L62-1. 71 (m, 2H), 1. 85-2. 00 (m, 2H), 2. 56 (s, 3H), 2. 81-3. 00 (m, 3H), 3. 24-3. 28 (m, 1H), 3. 34-3. 52 (m, 1H), 4. 02-4. 13 (m5 1H), 5. 58-5. 65 (m, 2H), 6. 72 (d, 1H), 7. 31 (s, 1H), 8. 19 (d, 1H) ; MH+ 301.  120858-110-200811169 Example 115 4_(2_Indolyl-3-propan-2-yl-imidazolium-4-yl)-N-[(3S)-l-methylsulfonyl-3-trihydropyridinyl] Pyrimidine-2-amine 4-(2-methyl-3-propan-2-yl-imidazolyl-4-yl)-N-[(3S)-3-hexahydropyridyl&gt;pyridine; amine (example) 112; 0·30 grams, 〇. 1 mM) and ΤΕΑ (0·21 ml, ι·5 mmol) were added to DCM (10 mL), then gasified methane sulfonate (0. 091 ml, 1. 2 millimoles). After stirring for 10 minutes, aq. EtOAc (3 mL)EtOAc. The title compound was obtained as a white solid (yield: m. 26 grams). NMR (400. 132 MHz, CDC13) 1. 56-1. 59 (m, 7H), 1·69-1·78 (m, 1H), 1. 89-2. 07 (m, 2H), 2. 57 (s, 3H), 2·78 (s, 3H), 2. 84-2. 92 (m, 1H), 2. 95-3. 09 (m, 1H), 3. 37-3. 46 (m, 1H), 3. 69-3. 72 (m, 1H), 4. 154. 23 (m, 1H), 5. 25 (d, 1H), 5. 57 (Seven peaks, 1H), 6. 77 (d5 1H), 7. 32 (s, 1H), 8. 21 (d,1H) ; MH+ 379 · Example 116 4-(2-Methyl-3-propan-2-yl--oxazol-4-yl)-N-[(3R)-1-methylsulfonyl- 3. Hexafluoropyridylpyrimidine-2-amine The title compound was obtained in a similar manner to Example 115 and using 4-(2-methyl-3-prop-2-yl-isoxazolyl)-N at a similar scale. -[(3R)-3-Hexidopyridyl]pyrimidin-2-amine (Example 1H) was prepared as a starting material. NMR (400. 132 MHz, CDC13) 1. 56-1. 66 (m, 7H), 1. 69-1. 78 (m, 1H), 1. 88-2. 00 (m, 2H), 2. 57 (s, 3H), 2. 78 (s, 3H), 2. 83-2. 94 (m, 1H), 2. 95-3. 08 (m, 1H), 3. 37-3. 46 (m, 1H), 3. 69-3. 72 (m, 1H), 4. 15-4. 23 (m5 1H), 5. 27 (d, 1H), 5. 56 (Seven peaks, 1H), 6. 77 (d, 120858 -Ill - 200811169 1H), 7. 32 (s,1Η)5 8·20 (d,1H) ; MH+ 379· Example 117 4_[[5-Alkyl-4-(2•methyl-3-propan-2-yl-isoxazole) Shouting pyridine: aryl] amide] hexahydrop than biting-1- retinoic acid third-butyl vinegar 2,5_di-gas-4-(2-mercapto-whenyl-2-yl-imidazolyl) (Method 6; 3 5 g, 12.9 mmol), hydrazine (3.95 ml, 28.4 mmol) and towyl-piperidine carboxylic acid tri-butyl ester (2. 84 grams, 14. 2 mmol) was added to DMA (8 mL) and heated at 100 °C for 16 hours. The solvent was evaporated to dryness to give a yellow gum. Water (100 ml) was added, then the mixture was extracted with DCM (3 χ 15 mM), and the combined organics were dried and dried, and solvent was removed in vacuo. The title compound was obtained as a yellow solid (5·5 g). ΜΗ+ 435· Example 118 5-Alkyl-4-(2-indolyl-3-propan-2-yl-isoxazole yl)·Ν_(4-hexahydropyridyl)pyrimidinamine 4-[[5 -Chloro-4-(2-methyl-3-propan-2-yl-imidazolidinyl)pyrimidin-2-yl]amino]hexahydropyridine-1-carboxylic acid tert-butyl ester (Example 117 ; 55 g, 129 mmol; dissolved in acetonitrile (30 ml), and added to a mixture of hexanes and hexanes (5 liters of hexane). The mixture was stirred for 2 hours, then evaporated to dryness. The resulting residue was dissolved in water (1 〇〇 liter), and solid NaHC 〇 3 was added until the reaction was tested (pH 9). The aqueous layer was then extracted with DCM (3 χ 2 〇〇). The combined organic material is dehydrated and dried, and the solvent is removed in vacuo to give a yellow solid which is dissolved in a minimum of hot acetonitrile and then cooled to dissolve the solid. This procedure was repeated to obtain the other two batches which were combined to give the title compound as a colourless solid (yield: 7g, 120858 - 112 - 200811169 85%). 132 MHz, CDC13) 1·40 (ddd, 2H), 1. 53 (d, 6H), 2. 00-2. 08 (m, 2H), 2. 58 (s, 3H), 2. 67-2. 73 (m, 2H), 3. 11 (ddd, 2H), 3. 82-3. 92 (m, 1H), 4. 89-5. 10 (m, 2H), 7. 48 (s, 1H), 8. 26 (s, 1H); MH+ 337.  Example 119 5-Alkyl_4-(2-methyl-3-propan-2-yloxazol-4-yl)-N-(l-methylsulfonyl-4-hexahydropyridyl)pyrimidine- The 2-amine title compound was used in a similar manner to Example 115 and utilized on a similar scale to give &lt;RTI ID=0.0&gt;&gt; (4-H-nitrogen p is prepared as a starting material than decyl-mididin-2-amine (Example 118). NMR (400. 132 MHz, CDC13) 1. 52 (d, 6H), 1. 64 (ddd, 2H), 2. 13-2. 17 (m, 2H), 2. 58 (s, 3H), 2·81 (s, 3H), 2. 85-2. 92 (m, 2H), 3, 75-3. 78 (m, 2H), 3·87_3·97 (m, 1H), 4. 90 (seven peaks, 1H), 5. 12 (d, 1H), 7·45 (s, 1H), 8. 29 (s, 1H) ; MH+ 415.  Example 120 5.··········································· )-4-hexahydropyridyl] shoutin-2-amine to give 5-a-based 4-(2-methyl-3-propan-2-yl-imidazolidyl)_N_(4-hexahydropyridinyl) Pyrimidine-2.amine (Example 118; 0. 2 grams, 0. 6 millimoles) with tea (0. 12 ml, 0. 90 mmol is dissolved in DCM (15 mL) and cooled to -1 °C. Slowly add gasification 2-ethane ethane sulfonate (0. 011 g, 〇·66 mmol, and the reaction was allowed to warm to ambient temperature and stirred for 30 min then EtOAc (2 mL). After stirring for 16 hours, the reaction mixture was evaporated to dryness eluting eluting elut elut elut elut elut eluting NMR (400. 132 MHz, CDCl3) U2 (d, 6h), L57_166 (4) 2H), 2. 10-2. 17 (m, 2H), 2. 27 (s, 6H), 2. 58 (s, 3H), 2·74-2·77 (m, 2H), 120858 -113- 200811169 2. 94-3. 01 (m, 2H), 3. 08-3. 12 (m, 2H), 3·76-3·79 (m, 2H) 5 3. 89-3. 97 (m, 1H), 4·90_4·93 (m, 1H), 5. 16 (s, 1H), 7. 46 (s, 1H), 8. 28 (s, 1H) ; MH+ 514.  Examples 121-123 The following compounds were prepared by the procedure of Example 120 and using the appropriate amines on the same scale. Example Compound NMR (400. 132 MHz, CDC13) m/z 121 5-Chloro-N-[H2-(4-methyl-1-hexahydrop-indenyl)ethyl sulphate]-4-hexahydro tonate]-4-( 2-methyl_3_propan-2-yl-imidazol-4-yl)pyrimidin-2-amine 0. 93 (d, 3H), 1· 17-1. 27 (m, 2Η), 1. 32-1. 43 (m, 1Η), 1. 52 (d, 6H), 1. 56-1. 67 (m, 4H), 1. 98-2. 17 (m, 4H), 2. 58 (s, 3H), 2. 78-2. 86 (m, 4H), 2. 94-3. 01 (m, 2H), 3. 12-3. 16 (m, 2H), 3. 75-3. 78 (m, 2H), 3. 87-3. 96 (m, 1H), 4. 91 (Seven peaks, 1H), 5. 07 (d, 1H), 7. 46 (s, 1H), 8. 28 (s,1H) 526 122 5-Gas-N-[l-(2-Dimethylaminoethyl-branched)-4-hexanitro? Ratio of 11 to 4-(2-methyl-3-propan-2-yl-sodium-4-yl)pyrimidine-2-amine 1. 52 (d, 6H), 1. 57-1. 66 (m, 2H), 2. 10-2. 17 (m, 2H), 2. 27 (s, 6H), 2. 58 (s, 3H), 2. 74-2. 77 (m, 2H), 2. 94-3. 01 (m, 2H), 3. 08-3. 12 (m, 2H), 3. 76-3. 79 (m, 2H), 3. 89-3. 97 (m5 1H), 4. 90-4. 93 (m, 1H), 5. 16 (s, 1H), 7·46 (s, 1H), 8. 28 (s,1H) 473 123 5_Chloro-4-(2-methyl-3-propan-2-yl-σmept-4-yl)-N-[l-(2-tetrahydrofolate 1 : mouth each -1-ylethyl aryl base)-4-hexahydropyridyl]pyrimidine-2-amine 1. 52 (d, 6H), 1. 56-1. 65 (m, 2H), 1. 79-1. 82 (m, 4H), 2. 10- 2. 13 (m, 2H), 2. 53-2. 56 (m, 4H), 2. 58 (s, 3H), 2. 89-3. 00 (m, 4H), 3. 14-3. 17 (m, 2H), 3. 76-3. 79 (m, 2H), 3. 88-3. 95 (m, 1H), 4. 89-4. 93 (m, 1H), 5. 11- 5. 12 (m, 1H), 7. 46 (s, 1H), 8. 28 (s,1H) 498 Example 124 5-Gas-Ν·[1_(3-methyl-3-nitro-butyl)sulfonyl-4-hexahydropyridyl]-4-(2-methyl 120858 -114- 200811169 _3-propan-2-yl-imidazolyl-4-ylpyrimidine-2-amine makes 5-chloro-4_(2-methyl-3-propan-2-yl-isoxazole_4 -yl)_N-(4-hexahydropyridyl) when pyridine-2-amine (Example 118; 0. 2 g, 0. 60 mM) was dissolved in DCM (7 mL) with TEA (〇 13 mL, 〇 9 mM). Slowly add 2 - chloroethane sulfonate (醯·〇7耄, 0. 66 Torr, and allowed to warm to ambient temperature and stirred for 30 minutes. The reaction mixture was evaporated to dryness and then dissolved in DMA (7 mL), followed by 1,8-diazabicyclo[5·4·〇]unda-7-ene (0. 191 grams, 1. 20 millimoles) with 2_Shi Xiaoji C. (0. 112 grams, ι·2〇 millim). The reaction was heated at 60 ° C for 30 minutes. Water was then added and the aqueous layer was extracted with DCm (3 X 50 mL), dried and dried and evaporated. Purification by flash chromatography on silica gel eluting EtOAc (EtOAc) NMR (400. 132 MHz, CDC13) 1. 52 (d, 6H), 1. 57-1. 66 (m, 8H), 2. 11-2. 15 (m, 2H), 2. 36-2. 41 (m, 2H), 2·58 (s, 3H), 2. 92-2. 97 (m, 2H), 2·99_3·03 (m, 2H), 3. 76-3. 79 (m, 2H), 3. 90-3. 99 (m, 1H), 4. 92 (seven peaks, 1H), 5·31-5. 37 (m, 1H), 7. 45 (s,1H),8·28 (s,1H) ; MH+ 516· Example 125 5_Fluoro-N-[l-(3_indolyl_3·decyl-butyl)-decyl-4- Hexahydro outside b butyl]-4_(2·methyl-3-propan-2-yl-miso-4-yl) ringing _2-amine title compound is in a similar manner to Example 124, and on a similar scale Using 5-Denyl·4-(2·decyl-3-propan-2-yl-flavored 4-yl)-indole-(4-hexahydro-exo-b-decyl)-glycin-2-amine ( Example 137) was prepared as a starting material. NMR (400. 132 ΜΗζ, CDC13) 1·55-1·64 (m, 14Η), 2. 14-2. 17 (m, 2Η), 2. 37-2. 41 (m, 2Η), 2·60 (S, 3H), 2. 92-3. 05 (m, 4H), 3. 77-3. 80 (m, 2H), 3. 85-3. 96 (m, 1H), 4.92 (d, 1H), 5. 49 (Seven peaks, 1H), 7. 53 (s,1H),8·16 (s,1H) ; MH+ 498· 120858 -115- 200811169 Example 126 N-[l_(3-Amino-3-methylbutyl)sulfonylhexylhexahydro Pyridyl bromide 5_gas-based ice (2-methyl-3-propan-2-yl-miso-4-yl) bite-2_amine makes 5-chloro-N-[l-(3-methyl- 3-Shool-butyl-butyl) hexyl hexahydrohydrocarbazide]-4-(2-methyl-3-propan-2-yl-isoxazole-4-yl)- phenanthridine-2-amine (Example 124 ; 189 mg, 0. 37 mmoles dissolved in acetic acid (20 ml) and iron (63 mg) was added thereto. 103⁄4 mol) and the reaction was heated at 60 C for 1 hour. then. The reaction was evaporated to dryness. EtOAc (EtOAc) (EtOAc) Yellow gum (0. 16 grams, 70%). MH+ 486.  Example 127 N-[l-(3-Amino-3-methyl-butyl)sulfonyl-4-hexahydropyridinyl]-5-fluoro-[4-(2-methyl-3-propanyl) 2_M--Miso-4-yl) Carbaryl-2-amine The title compound was obtained in a similar manner to Example 126, using 5-fluoro-N-[l-(3•methyl-3-) at a similar scale. Nitro-butyl)sulfonyl-4-hexahydropyridyl] ice (2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-amine (Example 125) as a starting point Made of matter. NMR (400. 132 MHz, CDC13) 1. 16 (s, 6H), 1. 45 (brs, 2H), 1. 55-1. 67 (m5 8H), 1·83-1·87 (m, 2H), 2. 12-2. 16 (m, 2H), 2. 60 (s, 3H), 2. 97-3. 08 (m, 4H), 3. 77-3. 80 (m, 2H), 3. 84-3. 93 (m, 1H), 4. 93 (d, 1H), 5·49 (seven peaks, 1H), 7. 52 (d, 1H), 8. 15 (d, 1H) ; MH+ 468.  Example 128 5-Gas-N-[l_(3-Diamylamino-3-methyl-butyl)sulfonyl-4-hexahydropyridyl]-4_(2-methyl-3-propan-2 -yl-imidazol-4-yl)pyrimidine-2.amine 120858-116- 200811169 Add MeOH (15 ml) and furfural (ΐ·〇 ml) to N-K3-amino-3-methyl-butyl Lucanyl-4-hexahydropyridyl]-5-chloro-[4-(2-indolyl-3-propan-2-yl-pyridin-4-yl)-l-pyridin-2-amine (Example 126; 160 mg, 0·33 mmol, followed by sodium cyanoborohydride (63 mg, 1. In 0 mmol, the reaction was stirred for 30 min then NaOH (20 mL) was added. The reaction was extracted with DCM (3×50 mL), dried and dried and evaporated. Purification by flash chromatography on silica gel eluting with EtOAc EtOAc (EtOAc) 068 grams, 44%). NMR (400. 132 MHz, CDC13) 1. 04 (s,6H),1·52 (d,6H),1·62 (ddd,2H),1. 88-1. 92 (m, 2H), 2. 10-2. 14 (m, 2H), 2. 21 (s, 6H), 2·58 (s, 3H), 2. 94-3. 04 (m, 4H), 3. 77 (d, 2H), 3. 88-3. 97 (m, 1H), 4. 91 (seven peaks, 1H), 5. 12-5. 19 (m, 1H), 7. 45 (s, 1H), 8. 28 (s, 1H) ; MH+ 514.  Example 129 N-[l_(3-Dimethylamino-3-methyl-butyl)sulfonyl-4-hexahydropyridyl] 5-fluoro-4-(2-methyl-3-propanyl) -2-yl-pyran-4-yl) ♦ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Butyl) phosphatidyl-4-hexanitroxanthyl bromide]-5-glycol (2-methyl-3-propan-2-yl-imidazolyl-4-yl)pyrimidine-2-amine (Example 127) Made as a starting material. NMR (400. 132 MHz, CDC13) 1. 03 (s, 6Η), 1. 55-1. 67 (m, 8H), 1. 88-1. 92 (m, 2H), 2. 12-2. 16 (m, 2H), 2·20 (s, 6H), 2. 60 (s, 3H), 2. 96-3. 04 (m5 4H) 5 3. 76-3. 79 (m5 2H)5 3. 83-3. 93 (m? 1H) 5 4. 99 (d? 1H)? 5. 50 (seven peaks, 1H), 7. 52 (d, 1H), 8. 15 (d,1H) ; MH+ 496· Example 130 5-Gas-N-[l-(3-dimethylaminopropylsulfonyl)-4-hexafluoropyridyl]_4_(2-methyl-3 - 120858 -117- 200811169 propyl-imidazolylpyrimidine-2•amine makes 5-chloro-4_(2_methyl_3_propan-2-yl-imidazolium-4-yl)-N_(4- Hexahydropyridyl) pyrimidine. Indoleamine (Example 118; L〇克, 2. 99 mM) and hydrazine (〇·62 ml, 4 5 mM mil) were dissolved in DCM (30 mL) and cooled to 1-1 °C. Among them, slow hydrazine added 2-chloropropane sulfonium chloride (0. 58 ml, 3. 29 mmoles, the reaction was allowed to heat to ambient temperature' and stirred for 3 minutes. Then, the reaction mixture was evaporated to dry EtOAc EtOAc EtOAc (EtOAc) The reaction was then evaporated to dryness eluting with EtOAc eluting NMR (400. 132 MHz, CDC13) 1. 52 (d, 6H), 1. 56-1. 66 (m, 2H), 1·93-2_00 (m, 2H), 2. 07-2. 15 (m, 2H), 2·22 (s, 6H), 2. 39 (t, 2H), 2. 58 (s, 3H), 2·94-3·02 (m, 4H), 3. 76-3. 79 (m, 2H), 3. 88-3. 95 (m, 1H), 4. 91 (seven peaks, 1H), 5. 30 (s, 1H), 7. 44 (s, 1H), 8. 28 (s, 1H); MH+ 486. Examples 131-134 The following compounds were prepared by the procedure of Example 13 and substituting the appropriate amine for the diamine at the same scale. Example Compound NMR (400. 132 MHz, CDC13) m/z 131 5-Chloro-indole (2-methyl-3-propan-2-yl-miso-4-yl)_N-[l-(3-tetrahydroindole ratio η丙基 醯 ) ) ) ) ) ) ) ) ) ) ) : ] ] ] ] ] ] ] ] ] 52 (d, 6H), 1.61 (ddd, 2H), 1 · 76·1. 79 (m, 4H), 1. 96-2. 04 (m, 2H) 5 2. 08-2. 15 (m? 2H) 5 2. 48-2. 51 (m, 4H), 2. 54-2. 58 (m, 5H), 2·94_3·05 (m, 4H), 3. 76-3. 79 (m, 2H) 5 3. 88-3. 95 (m, 1H), 4. 91 (seven peaks, 1H), 5. 23 (s, 1H), 7·45 (s, 1H), 8·28 (s, 1H) 512 120858 -118- 200811169 Example Compound NMR (400. 132 MHz, CDC13) m/z 132 5-chloro-4-(2-methyl-3-propan-2-yl-imidazolium-4-yl)-N-[l-[3-(l-hexachloro) P is more specific than sigma) propylsulfonyl]-4-hexahydro^: σ定基] mouth bite-2-amine 1. 42-1. 46 (m, 2H), 1. 51-1. 66 (m, 10H), 1. 93-2. 00 (m, 2H), 2. 09-2. 13 (m, 2H), 2. 35-2. 42 (m, 8H), 2. 58 (s, 3H), 2. 93-3. 02 (m, 4H) 5 3. 76-3. 79 (m? 2H) 5 3. 88-3. 97 (m, 1H), 4. 91 (seven peaks, 1H), 5·26 (s, 1H) 5 7·45 (s, 1H), 8. 28 (s,1H) 526 133 5-Gas-N-[l-[3-(4-methylhexahydrop-well-1_yl)propylindolyl]-4-hexahydrop-ratio σ-based] 4-(2-methyl-3-propan-2-yl-imidazolidyl)pyrimidine-2-amine 1. 52 (d, 6H), 1. 61 (ddd, 2H), 1. 94-2. 01 (m, 2H), 2. 10-2. 14 (m, 2H), 2. 28 (s, 3H), 2. 41-2. 53 (m, 10H), 2. 58 (s, 3H), 2. 93-3. 02 (m, 4H), 3. 75-3. 78 (m, 2H), 3. 88-3. 97 (m, 1H), 4. 90 (Seven peaks, 1H), 5. 23 (s, 1H), 7·44 (s5 1H), 8. 28 (s,1H) 541 134 5·Chloroi-4-(2-methyl-3-propan-2-yl-indole. Sodium-4-yl)-indole-indole (3-norfos-4) Propyl hexahydropyridylpyrimidin-2-amine 52 (d, 6H), 1. 61 (ddd, 2H), 1. 95-2. 02 (m, 2H), 2. 08-2. 16 (m, 2H), 2. 42-2. 47 (m, 6H), 2. 58 (s, 3H), 2. 93-3. 03 (m, 4H), 3. 70 (m, 4H), 3. 76_3. 79 (m, 2H), 3. 89-3. 96 (m, 1H), 4. 90 (seven peaks, 1H), 5·26 (s, 1H), 7. 44 (s, 1H), 8. 28 (s, 1H) 528 Example 135 4_[[5_气基冬(2-Methyl:Cet-2-yl-oxazolidine) 喊 ::yl]amino]hexahydropyridin-1_carboxylate Benzyl benzoate sequestered 2-yl-5-fluoro-4-(2-indolyl-3-propan-2-yljm-4-yl)u (Method 8; 10 g' 39. 4 millimoles), DIPEA (15. 4 ml, 86·7 mmoles) and 4-aminohexahydropyridine-1-carboxylic acid benzyl ester (11. 0 g, 47 2 mmol) was added to DMA (200 mL) and heated at 125 ι for 2 days. The reaction mixture was evaporated to dry <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 120858-119-200811169 It was dissolved in DCM, propan-2-ol was added, and then DCM was slowly evaporated to give a solid. This was overdrawn and washed with ether, and the procedure was repeated using EtOAc to give two additional crops which were combined to give the title compound as a white solid (13. 75 grams). NMR (400. 132 MHz, CDC13) 1. 38-1. 48 (m, 2H), 1. 55 (d, 6H), 2. 03-2. 06 (m, 2H), 2·60 (s, 3H), 3·00 (t, 2H), 3. 85-3. 94 (m, 1H), 4. 13-4. 16 (m, 2H), 4. 90 (d, 1H), 5. 14 (s, 2H), 5. 54 (Seven peaks, 1H), 7. 29-7. 37 (m, 5H), 7. 52 (d, 1H), 8·15 (d, 1H); MH+ 453.  Example 136 4- [[5-Fluoro-4-(2-methyl-3·propan-2-yl-miso-based)--------------------- -Butyl ester is 2-oxo-5-fluoro-4-(2.methyl-3-propan-2-yl----------------------------- 0 grams, 21. 7 millimoles), TEA (6. 03 ml, 43. 3 mmoles and 4-aminopiperidine-1·carboxylic acid tert-butyl ester (4. 33 grams, 21. 7 mmoles was added to DMA (80 ml) and heated at ii ° °c for 2 days. The solvent was evaporated to dryness to give a yellow gum, water (100 ml) was added, and the aqueous layer was extracted with DCM (3 X 150 liters). The combined organic material was dehydrated and dried, and the solvent was removed in vacuo to give a yellow solid. 2 grams, 87%). MH+ 419.  Example 137 5-Fluoro-4-(2-methyl-3.propan-2-yl-isoxyl-4-yl)hexahydropyridyl)pyrimidine-2-amine 4 of EtOH (700 mL) -[[5_Fluorine (2_methyl-3-propan-2-yl)imidazole)3⁄4 °定-2·yl]amino]6虱峨 bit-1--1- 酸 爷(Example I%; 13. 75 grams, 30. 4 millimoles) and l〇% Pd/C (1. 3 g), stirred at 25 ° C and 5 bar of hydrogen under pressure for 18 hours. The reaction mixture was filtered through celite, and was evaporated in vacuo to give a yellow solid. It was dissolved in hot acetonitrile and then cooled to precipitate a solid which was filtered and dried. This procedure was repeated using the filtrate to give additional material, which was combined to give the title compound as a colourless solid (7·5 g). NMR (400. 132 MHz, CDC13) 1. 41 (ddd, 2H), 1. 56 (d, 6H), 2. 04-2. 06 (m, 2H), 2. 60 (s, 3H), 2·71 (t, 2H), 3·00-3·15 (m, 2H), 3. 78-3. 87 (m, 1H), 4. 95 (d, 1H), 5. 59-5. 62 (m, 1H), 7·53 (d, 1H), 8. 14 (d, 1H) ; MH+ 319.  Example 138 5-Fluoro-4-(2•methyl-3-propan-2-yl·miso-4-yl)-N-(l-methyl-indolyl-4-hexahydropyridyl)pyrimidine- 2-amine gives 1-methanesulfonyl hexahydropyridinamide (0. 098 g, 0·55 mmol, suspended in isopropanol (2 ml), then 2-chloro-5-fluoro-4-(2-mercapto-3-propanyl-imidazole-4 -based &gt; pyridine (Method 8; 70 mg, 0. 27 millimoles), TEA (0. 11 ml, 0·82 mmol, sodium iodide (12 mg, 〇_〇 8 mmol), and under ι6 〇 C, the mixture was heated by microwave for 5 Torr. The solvent was removed in vacuo and purified by flash chromatography on silica gel eluting with gradient gradient The title compound was obtained as a creamy solid (52 g, 48%). NMR (4〇〇 132 MHz, CDCl3) ! 48 (d,6H),i % (m,2H), 2·10 (m,2H),2. 53 (s, 3H), 2. 75 (s, 3H), 2. 84 (m, 2H), 3. 70 (m, 2H), 3. 81 (m, 1H), 4. 81 (d, 1H), 5. 41 (m, m), 7. 45 (d, 1H), 8. G9 (d, 1H) ; MH+ 397.  Example 139 N [1-(2-monoethylaminoethyl) hexamethylene hydrazide]_5_fluoroyl_4_(2_mercapto-1 propan-2-yl-isoxazole ice-based) Pyridin-2-amine 120858 -121 - 200811169 5-fluoro-4-(2-methyl-3-propan-2-yl-isoxazole)-N-(4-hexahydropyridyl)pyrimidine_2 The amine (Example 137; 200 mg, 〇 · 62 mmol) was dissolved in dcm and added TEA (0. 26 ml, 1. 87 millimoles) and allowed to cool the reaction to hydrazine. . . Will be chlorinated 2-chloroethane sulfonate (〇. 〇 8 ml, 〇 75 mM was added dropwise to the cooled solution, and the reaction was stirred for 20 minutes, then dimethylamine (1 mL) in Me 〇H was added. After stirring for 1 h, the solvent was evaporated in vacuo. NMR (400. 132 MHz, CDC13) 1. 55-1. 66 (m, 8H), 2. 11-2. 15 (m, 2H), 2. 28 (s, 6H), 2. 60 (s, 3H), 2. 74-2. 78 (m, 2H), 2. 96-3. 02 (m, 2H), 3·09-3·12 (m, 2H), 3. 76-3. 79 (m, 2H), 3. 84_3_93 (m, 1H), 4. 99 (d, 1H), 5. 50 (seven peaks, 1H), 7. 52 (d, 1H), 8. 15 (d, 1H) ; MH+ 454.  Examples 140 to 142 The following compounds were prepared by the procedure of Example 139 and using the appropriate amines on the same scale. Example Compound NMR (400. 132 MHz, CDC13) 140 5-fluoro-based 4-(2-mercapto-3-propan-2-yl-.saltyl) !&gt;0 tetrahydropyrrole_1-ylethylsulfonyl&gt; 4-hexahydropyridyl 11-based] guanidine-2-amine 1. 55-1. 66 (m, 8H), 1. 77-1. 83 (m, 4H), 2. 11-2. 15 (m, 2H), 2. 52-2. 58 (m, 4H), 2. 60 (s, 3H), 2. 90-2. 94 (m, 2H), 2. 96-3. 02 (m, 2H), 3·14·3·18 (m, 2H), 3. 76-3. 79 (m? 2H)? 3. 83-3. 92 (m, 1H), 4. 94 (d, 1H), 5. 49 (Seven peaks, 1H), 7. 52 (d, 1H), 8. 15 (d,1H) 120858 -122- 200811169 Examples Compound NMR (400. 132 MHz, CDC13) m/z 141 Ν·[1-[2-(7-nitrobicyclo[2. 2. 1]hept-7-yl)ethyl phosphatidyl]-4-hexachloropyrene than sigma]-5-fluoro-4-(2-methyl-3-propan-2-yl-.mist-4-yl ) 唆-2-amine 1. 35 (d, 4H), 1. 55-1. 66 (m, 8H), 1. 70-1 · 77 (m, 2H), 1. 94 (s, 2H), 2. 11-2. 17 (m, 2H), 2. 60 (s, 3H), 2. 79-2. 83 (m, 2H), 2. 96-3. 03 (m, 2H), 3. 11-3. 15 (m, 2H), 3. 26-3. 28 (m, 2H), 3. 75-3. 80 (m, 2H), 3. 82-3. 91 (m, 1H), 4. 96 (d, 1H), 5. 49 (seven peaks, 1H), 7_52 (d, 1H), 8. 15 (d,1H) 506 142 Ν-[1·[2-(6-azabicyclo[2·2·2]oct-6-yl)ethylsulfonic acid]-4-hexanitrogen ]-5-Api-4-(2-methyl-3-propan-2-yl-indolyl-4-yl)pyrimidin-2-amine 1. 47-1. 66 (m, 14H), 1. 86-1. 95 (m, 4H), 2. 11-2. 16 (m, 2H), 2. 60 (s, 3H), 2. 70-2. 73 (m, 2H), 2. 92-3. 03 (m, 4H), 3. 09-3. 13 (m, 2H), 3. 76-3. 80 (m, 2H), 3. 83-3. 92 (m, 1H), 4. 98 (d, 1H), 5. 49 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d,1H) 520 Example 143 [·[1-(3-Actylpropyl)-4-hexanitrocarbazide]-5-fluoro-4-(2-methyl-3- Propyl-2-yl-imidazol-4-ylpyrimidin-2-amine gives 5-fluoro-4-(2-methyl-3-propan-2-yl-imidazolium)-N-(4-hexa) Hydropyridyl)pyrimidin-2-amine (Example 137; 0 grams, 3. 14 millimoles) with TEA (0. 66 ml, 4. 71 mmoles dissolved in DCM (30 mL) and cooled to -10 °C. Add 2-chloropropane chlorination 醯 (0. 66 ml, 4. 71 mmol) and the reaction was allowed to warm to ambient temperature and stirred for 30 min. The reaction was evaporated to dryness eluting elut elut elut elut elut elut elut elut elut elut elut elut elut NMR (400. 132 MHz, CDC13) 1. 55-1. 67 (m, 8H), 2. 13-2. 17 (m, 2H), 2. 26-2. 33 (m, 2H), 2. 60 (s5 3H), 2. 97-3. 04 (m5 2H), 3. 11 (t, 2H), 3. 70 (t, 2H), 3. 78-3. 81 (m, 2H), 3. 85-3. 94 (m, 1H), 4. 95 120858 -123- 200811169 (d,1H),5·49 (Seven peaks, 1H), 7. 52 (d, 1H), 8. 15 (d, 1H) ; MH+ 459.  Example 144 Ν·[1-(3-Dimethylaminopropyl hydrazino)-4-hexahydropi ratio thiophenylidene-3-yl-2-yl-miso-4-yl) Shouting bite-2-amine to dimethylamine in MeOH (1. 0 ml) was added to N-[l_(3-cyclopropylsulfonyl)-4-hexamethylpyridinium]-5-fluoro-4-(2-methyl-3-propan-2-yl) - Miso-4-based ketone-2-amine (Example 143; 0. 14 grams, 0. 31 mmoles in a solution of DMA (10 mL) and heated at 90 °C for 16 hours. The reaction was then evaporated to dryness eluting elut elut elut elut elut elut eluting NMR (400. 132 MHz, CDC13) 1. 55-1. 67 (m, 8H), 1. 94-2. 01 (m, 2H), 2. 11-2. 15 (m, 2H), 2. 22 (s, 6H), 2. 39 (t, 2H), 2. 60 (s, 3H), 2. 95-3. 02 (m, 4H), 3. 76-3. 79 (m, 2H), 3. 83-3. 92 (m, 1H), 5. 06 (d, 1H), 5. 50 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d, 1H) ; MH+ 468.  Examples 145 to 166 The following compounds were prepared by the procedure of Example 144 and using the appropriate amines on the same scale. Example Compound NMR (400. 132 MHz, CDC13) m/z 145 5_gas-based-4-(2-mercaptopropan-2-yl-flavor σ sitting_4_yl)_N-[1-(3_tetrahydrop bilo-1 _ propyl sulfonyl group &gt; 4-hexahydropyridyl] pyrimidine-2-amine 1. 55-1. 66 (m, 8H), 1. 77-1. 80 (m, 4H), 1·98_2·〇5 (m, 2H), 2. 11-2. 15 (m, 2H), 2. 50-2. 53 (m5 4H), 2·56_2·60 (m, 5H), 2. 94-3. 06 (m, 4H), 3. 77 (d, 2H), 3. 83-3. 92 (m, 1H), 5. 05 (d, 1H), 5. 50 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d,1H) 494 —----- 120858 -124- 200811169 Example Compound NMR (4(10). 132 MHz, CDC13) m/z 146 5-decyl-4-(2-methyl-3-propan-2-yl-flavor 11 -4-yl)-N-[l-[3-(1- Six rat ρ ratio σ 基 ) 丙基 醯 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 41-1. 46 (m, 2H)? 1. 52-1. 66 (m, 12H), 1. 94-2. 01 (m, 2H), 2. 11-2. 15 (m3 2H) 5 2. 32-2. 42 (m, 6H), 2·60 (s, 3H), 2. 94-3. 03 (m, 4H), 3. 76-3. 79 (m, 2H), 3. 84-3. 92 (m, 1H), 5. 06 (d, 1H), 5. 50 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d,1H) 508 147 5-Fluoro-N-[l-[3-(4-methylhexahydropyrrolidin-1-yl)propylsulfonyl]-4-hexahydrop-indenyl] 4-(2-methyl-3-propan-2-yl-m-mythazole-4-yl)pyrimidine-2-amine 1. 55-1. 67 (m, 8H), 1. 94-2. 02 (m, 2H), 2. 11-2. 15 (m, 2H), 2. 29 (s, 3H), 2. 44-2. 56 (m, 10H)? 2. 60 (s5 3H)? 2. 94-3. 03 (m, 4H), 3. 75-3. 78 (m, 2H), 3. 84-3. 93 (m, 1H), 5. 09 (d, 1H), 5. 49 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d,1H) 523 148 5-Alkyl-4-(2-methyl-3-propan-2-yl-imidazol-4-yl(3-moff-4-ylpropyl sulphate)-4 - hexahydro-p ratio. Stationary] pyrimidine-2_amine 1. 55-1. 67 (m, 8H), 1. 95-2. 02 (m, 2H), 2. 12-2. 16 (m, 2H), 2. 42-2. 47 (m, 6H), 2·60 (s, 3H), 2. 94-3. 04 (m, 4H) 5 3. 69-3. 71 (m, 4H), 3. 75-3. 79 (m, 2H), 3. 84-3. 93 (m, 1H), 5. 08 (d, 1H), 5. 48 (seven peaks, 1H), 7. 51 (d, 1H), 8. 15 (d,1H) 510 149 N-[l-[3-(6_l bicyclo[2·2·2]oct-6-yl)propyl fluorescene]-4-hexafluoropyrene]_5 _Fluoro-4-(2-methyl-3-propan-2-yl. koumijun_4_yl) ϋ密咬-2-amine 1. 44-1. 66 (m, 15H), 1. 87-1. 97 (m, 4H), 2. 11-2. 15 (m, 2H), 2. 48-2. 51 (m, 1H), 2. 58-2. 61 (m, 5H), 2. 68 (s, 2H), 3. 07-2. 95 (m, 4H), 3. 76-3. 79 (m, 2H), 3. 84-3. 93 (m, 1H), 4. 98 (d, 1H), 5. 50 (seven peaks, 1H), 7. 52 (d,1H),8·15 (d,1H) 534 120858 125- 200811169 Example Compound NMR (400. 132 MHz, CDC13) m/z 150 N-[l-[3-(7-azabicyclo[2. 2. 1]hept-7-yl)propylsulfonyl]-4.hexahydrop-pyridyl]-5-f--4-(2-methyl-3-propan-2-yl-[alpha]-4 - base) ϋ σ determinate-2-amine 1. 28-1. 29 (m, 5H), 1. 55-1. 71 (m, 11H), 1.92_1·99 (m, 2H), 2. 11-2. 15 (m5 2H), 2·45 (t, 2H), 2. 60 (s, 3H), 2. 95-3. 02 (m, 2H), 3. 06-3. 10 (m, 2H), 3. 23-3. 25 (m, 2H), 3. 76-3. 80 (m, 2H), 3. 84-3. 93 (m, 1H), 5. 03 (d, 1H), 5. 50 f Qifeng, 1H), 7. 52 (d,1H),8·15 (d,1H) 520 151 N-[l-[3-(cyclopropylamino)propylsulfonyl]-4-hexahydropyridinyl]-5-fluoro -4-(2-methyl-3-propan-2-yl-miso^--4-yl)pyrimidin-2-amine (DMSO) 0. 18-0. 22 (m? 2H)? 0. 34-0. 38 (m, 2H), 1. 49-1. 51 (m, 7H), 1. 52-1. 59 (m, 2H), 1. 76-1. 83 (m, 2H), 1.95 (d, 2H), 2. 01-2. 05 (m, 1H), 2. 49 (s, 3H), 2. 66 (t, 2H), 2. 88 (t, 3H), 3. 04-3. 08 (m, 2H), 3. 62 (s, 2H), 3. 78 (t, 1H), 5. 43 (s, 1H), 7. 22 (s, 1H), 7. 32 (d, 1H), 8. 37 (d, 1H) 480 152 N-[l-[3-(cyclopentylamino)propylsulfonyl]-4-hexahydropurine 匕 定]]-5-乱基-4-(2- Methyl-3-propan-2-ylmicarbazin-4-yl)pyrimidine-2_amine 508 Ν[[1-[3-(cyclobutylamino)propyl)]-4-hexahydro P-bite base]-5-carbyl-4-(2-methyl_3_propan-2-ylmist-4-yl)pyrimidine-2-amine (DMSO) 1. 49-1. 51 (m, 6H), 1-52-1. 83 (m, 9H), 1. 96 (d, 2H), 2. 06-2. 12 (m, 2H), 2·50 (s, 3H), 2. 90 (d, 2H), 3. 05-3. 09 (m, 2H), 3. 12 (t,1H),3·18_3·19 (m,1H),3·61 (d,2H),3. 79 (t, 1H), 5. 43 (s, 1H), 7·23 (s5 1H), 7·32 (d, 1H), 8. 36-8. 37 (m,1H) 494 154 5_sayyl-4-(2-indolyl-3-propan-2-yl-sodium-4-yl)-N-[l-[3-^ _2-ylamine Propylsulfonyl]-4.hexahydropyridinylpyrimidin-2-amine 482 120858-126- 200811169 Example compound NMR (400. 132 MHz, CDC13) m/z 155 5-fluoro-Ν-[1-[3-(methyl-propan-2-yl-amino)propylsulfonyl]-4-hexazone sigma]- 4-(2-methyl-3-propan-2-yl-imida-4-yl) oxime-2-amine 496 156 3-[3-[[4-[[5·fluoro-4-( 2-methyl-3-propan-2-yl-flavor.All-4-yl)η密ϋ定-2-yl]amino]-ΙΑ Nitrogen? More than 17 bases] propyl-methyl-amino]propionitrile 507 157 N-[l-[3-(mononitrotetrayl-1-yl)propyl acid]-4-hexahydro Pyridyl]-5-fluoro-4-(2-methyl-3-propan-2-yl-imida-4-yl)bitat-2-amine 480 Ν-[1·[3-(B -methyl-amino)propylsulfonyl]-4-hexahydropyridyl]-5-fluoro-4-(2-mercapto-3-propan-2-yl-mouth saliva-4 - Base) continued. -2-amine 482 159 N-[l-(3-diethylaminopropyl fluorescein)-4-hexanitropyranyl]-5-fluoro-4-(2-methyl-3) -propan-2-yl-miso-4-yl)pyrimidine-2-amine 496 160 N-[l-[3-(cyclopropyl-methylamino)propyl)]_4_ hexahydro^ Specific sigma]-5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidine-2-amine 494 120858 127- 200811169 Example compound NMR (400. 132 MHz, CDC13) m/z 161 5-Fluoro-N-[l-[3-(2-decyloxyethyl-methyl-amino)propyl fluorescene]-4-6 rat batch ]-4_(2-methyl-3-propan-2-yl-miso-4-pyrimidin-2-amine 512 162 3-[ethyl-[3-[[4-[[5-fluoro] 4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]-1-hexanitrogen-pyridyl]sulfonic acid]propyl] Amino] propionitrile 521 163 Ν-[1-[3-(Ν-cyclopentyl-fluorenyl-methyl-amino)propylsulfonyl]-4-hexanitro-p-r-butyryl]-5-like 4-(2-methyl-3-propan-2-yl-imidazolidinyl)pyrimidin-2-amine 522 164 N-[1-|&gt;(N-cyclopropyl-N-methyl-amino group Propylsulfonyl]-4-hexaquinone sigma-based]-5-carbyl-4-(2-methyl-3-propan-2-yl-mist-4-yl) mouth bite-2- Amine 494 165 Ν-[1-[3-(Ν-cyclobutyl-N-methyl-amino)propylsulfonyl]-4-hexahydropyridyl]-5-carbyl-4-(2 _Methyl-3-propan-2-yl-flavor n-seat 4-yl) sputum 2- 2-amine 508 120858 128- 200811169 Example compound NMR (400. 132 MHz, CDC13) m/z 166 Ν-[1-[3-(Ν-cyclopropylmethyl-indole-methyl-amino)propyl fluorescein]-4-hexahydroindenyl]- 5-fluoro-4-(2-methyl-3-propan-2-ylamine. Sodium-4-yl hydrazin-2-amine 508 Example 167 4_[[5-Fluoro- 4_(2-methyl) _3_propyl-isazole_4_yl) shhidine_2_yl]amino]_N_(2_tetrahydrofuro-1_ylethyl)hexahydropyrene than bite_1·jhenamine 5 -Fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-indole-(4-hexahydropyridinyl)pyrimidin-2-amine (Example 137) with TEA (0 . 044 ml, 0. 31 mmoles) The solution in DCM (3 liters) was cooled to -78 ° C and sulphur dichloride was added dropwise (0. 026 ml, 0_31 millimoles). The mixture was stirred at j78 〇c for 15 minutes, then allowed to warm to ambient temperature and ΤΕΑ (0·〇 44 mL, 0. 31 mM) with 1-(2-aminoethyl)tetrahydropyrrole (44 mg, 〇·38 mmol). After stirring for 6 hours, DCM (7 mL) was added and the mixture was washed with water. The aqueous layer was washed with additional DCM (5 mL) and the combined organic material was passed through a phase separation film and evaporated in vacuo. The residue was purified by EtOAc (EtOAc EtOAc) Nmr (CDC135 400. 132 MHz) 1. 52-1. 65 (m5 9H) 5 1. 74-1. 81 (m? 4H)? 2. 08-2. 17 (m, 2H), 2·47-2·56 (m, 4H), 2. 60 (s, 3H), 2. 64 (t, 2H), 2. 95 (t, 2H), 3. 12 (t, 2H), 3. 70 (d, 2H), 3. 80-3. 92 (m, 1H), 4·89 (d, 1H), 5. 46-5. 59 (m, 1H), 7. 53 (d,1H), 8·15 (d,1H) ; MH+ 495.  Examples 168 to 182 The following compounds were prepared by the procedure of Example 167 and used at the same scale using 120858-129-200811169. Example Compound NMR (400. 132 MHz, CDCI3) m/z 168 N_(2-diethylaminoethyl)_4_[[5-fluoro-4-(2•methyl-3-propan-2-ylmidin-4-yl) [pyridine-2-yl]amino] hexahydro ton bite-1-continued guanamine 1. 02 (t, 6H), 1. 50-1. 68 (m, 10H), 2. 13 (d, 2H), 2. 53 (q, 4H), 2. 57-2. 62 (m, 4H), 2_94 (t, 2H), 3. 06 (t, 2H), 3. 70 (d, 2H), 3. 80-3. 91 (m, 1H), 4. 90 (d, 1H), 5. 46-5. 59 (m, 1H), 7. 52 (d, 1H), 8. 15 (d,1H) 497 169 4_[[5-fluoro-4-(2-methyl-3-propan-2-yl-isosyl) pyrimidinyl]amino]-N-(2- Morphine _4_ylethyl) hexahydropyridine small decylamine 511 170 4-[[5-alkyl-4-(2-methyl-3-propan-2-yl·^m-sal-4- Pyrimidine-2-yl]amino]-N-[2-(4-methylhexahydroport ratio p- well-1_yl)ethyl]hexahydroP-pyridyl-1_sulfonamide 524 171 4 -[[5-fluoro-4-(2-mercapto-3-propan-2-yl-methyl-pyran-4-yl)pyrimidin-2-yl]amino]-N-(3-tetrahydro) Pyrrol-1-ylpropyl)hexaquinone" is 0-1 - sulfonamide 509 172 N-(3-dimethylamino 2,2-dimethyl-propyl)-4-[[5· Fluoro-4-(2.methyl-3-propan-2-yl-umia sitting on _4_yl). 密π定_2_ yl]amino] hexahydroindole 1 bite-1-stone yellow Amine 511 120858 -130- 200811169 Example compound NMR (400. 132 MHz, CDC13) m/z 173 4-[[5-fluoro-4-(2-mercapto-3-propan-2-yl-.m--4-yl)pyrimidin-2-yl]amine ]]-N-[3-〇 hexahydroindole) propyl] hexahydron-l-sulfonamide 1. 37-1. 64 (m, 14H), 1_71 (t, 2H), 3·11 (d, 2H), 2. 31-2. 53 (m, 6Η), 2. 60 (s, 3Η), 2.92 (t, 2H), 3·17 (t, 2H), 3.68 (d, 2H), 3. 80-3. 91 (m, 1H), 4. 88 (d, 1H), 5. 48-5. 60 (m, 1H), 7. 53 (d, 1H), 8. 15 (d,1H) 523 174 4-[[5-Fluoro-4-(2-methyl-3-propan-2-yl-m-methane-4-yl)pyrimidin-2-yl]amino] -N-[3-[(3S)-3-fluorotetrahydropyrrol-1-yl]propyl]hexazone b 17-1- or yellow amine 527 175 N-(3-dimethylamino -propyl hydrazine-[[5.fluoro-4-(2-methyl-3.propan-2-yl-methyl-4-yl)pyrimidin-2-yl]amino]methyl-hexahydro ρ pyridine-1-sulfonamide 497 176 4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-indolyl-4-yl)pyrimidin-2-yl]amine ]]-N-[2-(1•methyltetrahydrop-bi-2-yl)ethyl]hexahydropyridin-1-ylamine 509 177 4-[[5-fluoro-4-( 2-methyl-3·propan-2-yl-miso-4-yl)pyrimidin-2-yl]amino]-N-(1-methyl-4-hexahydrop-bite) hexahydro Said sigma-1 -sulfonamide 495 120858 -131 - 200811169 Example compound NMR (400. 132 MHz, CDC13) m/z 178 4-[[5- sylylene (2-methyl-3-propan-2-yl- sigyl-4-yl)pyrimidin-2-yl]amino]- Ν_ (1-propan-2-yl-4-hexahydropurine 匕 定 )) hexahydro ρ than bite-1-glycoside 523 179 N-[l-[(3R)-3-dimethylamino four Hydropyrrolidin-1-yl]sulfonyl-4-hexahydrop to dimethyl]-5-yl-4-(2-methyl-3-propan-2-yl-gumazine-4-yl)pyrimidine -2-amine 48-1. 61 (m, 7H), 1. 77-1. 90 (m, 1H), 2. 07-2. 17 (m, 3H), 2. 26 (s, 6H), 2·60 (s, 3H), 2. 37-2. 84 (m, 1H), 2. 97 (t, 2H), 3. 09 (t, 1H), 3. 34 (appq, 2H), 3·46 (apparent, 1H), 3_56 (apparent, 1H), 3·64-3·74 (m, 2H), 3·80-3·92 (m, 1H) , 4·89 (d, 1H), 5. 46-5. 58 (m, 1H), 7. 53 (d, 1H), 8. 15 (d,1H) 495 180 5-Fluoro-N-[l-[(4-methyl-1,4-diaza sulphide-1-yl) sulphate]-4-hexapyridinyl ]-4-(2-mercapto-3-propan-2-yl-ηm. sit-4-yl)glycin-2-amine 495 181 5-fluoro-N-[l-(4_曱基六Exo-b P well-1-yl) continued S-toileyl-4-hexanitro-p-indenyl]-4-(2-methyl-3-propan-2-yl-11-mistylpyrimidin-2-pyrimidin-2- Amine 54-1. 63 (m, 7H), 2. 10 (m, 3H), 2. 32 (s, 3H), 2. 46 (t, 4H), 2. 60 (s, 3H), 2. 98 (t, 2H), 3. 28 (t? 4H) 5 3. 71 (d5 2H)? 3. 80-3. 92 (m, 1H), 4. 87 (d, 1H), 4. 46-5. 57 (m, 1H), 7. 53 (d, 1H), 8. 15 (d,1H) 481 182 N-(2-dimethylamino-ethyl) ice [[5-1-based 4-(2-methyl-3-prop-2-yl). Pyrimido-2-yl]amino] hexahydropyridine-1-sulfonamide 469 Example 183 3-[[4-[[5-Alkyl-4-(2methyl-3-prop-2-yl) - 嗤-4-基), 咬_2_基]胺基]·1-120858 -132- 200811169 hexahydropyranyl] hydrazinyl] hexahydropyridine-1-carboxylic acid 5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-N-(4-hexahydropyridinyl)pyrimidin-2-amine (Example 137; 5 grams, 1. 57 millimoles) with TEA (0. 33 ml, 2. 35 mM dissolved in DCM (50 mL), then added 3_(chlorosulfonyl fluorenyl) hexahydroindole 1,4--1-carboxylic acid ester (Preparation 62 in W099/45006; 0. 82 grams, 2. 35 millimoles). The reaction was dropped for 1 hour' and then evaporated to dryness and passed through a SCX column. Then, the obtained material was purified by flash chromatography eluting with EtOAc EtOAc EtOAc 4 grams, 41%). MH+ 614.  Example 184 4-[[4-[[5-Fluoro-4-(2-methyl_3_propan-2-yl-miso-4-yl), dimethyl-2-yl]amino]-1 Benzyl hexahydropyridyl]sulfonyl] hexahydropyridine _1-carboxylate benzyl 4-chlorosulfonyl hexahydropyridine _1-carboxylate in DCM (3 mL) at ambient temperature ( 334 mg) was added dropwise to 5-fluoro-based ice (2·methyl-3-propan-2-yl-imidol-4-yl)-Ν·(4-hexahydro-p-bite) 唆-2- The amine (Example 137; 318 mg) was taken in a stirred solution of TEA (202 mg) in anhydrous DCM (9 mL). After 2 hours, the mixture was diluted with aq. sat. NaHC.sub.3 and extracted with DCM. The extract was dehydrated, concentrated, and purified by flash chromatography eluting eluting eluting eluting eluting NMR (400. 13 MHz, CDC13) 1·50·1·80 (m5 10H), 2. 10 (m, 4H), 2. 60 (s, 3H), 2·80 (m, 2H), 3·05 (m, 3H), 3. 79 (m, 2H), 3. 90 (m, 1H), 4. 35 (m, 2H), 4. 90 (d, 1H), 5. 13 (s, 2H), 5. 50 (m, 1H), 7. 37 (m, 5H), 7. 52 (d, 1H), 8. 15 (d, 1H) ; MH+ 600.  Example 185 120858 -133 - 200811169 5_Fluoroyl winter (2_methyl_3_propan-2-yl-imidazole-4-yl)_]^_[1-(4_hexahydropyridylsulfonyl) 4-[hexahydropyridyl]pyrimidin-2-amine 4-[[4-[[5-fluoro-4-(2-methyl-3.propan-2-yl) in MeOH (16 liter) "Mizozolidine" pyrimidine-2-yl]amino] hexahydropyridyl] sulfhydryl hexahydropyridine small carboxylic acid vinegar (Example 184; 480 mg), using H_CUBE system (Thales Nanotechnology), 10% Pd/C cartridge, hydrogenated at 5 (rc, using full flow of hydrogen (1 bar, 1 mL/min). The solvent was evaporated to give the product as a gum (344 t, 92%). 13 MHz, CDC13) 1. 5 (M. 75 (m, 10H), 2. 08 (m, 4H), 2. 60 (m, 5H), 3·08 (m, 3H), 3·22 (m, 2H), 3. 82 (m, 2H), 3·91 (m, 1H), 4·92 (d, 1H), 5·50 (m, 1H), 7. 52 (d, 1H), 8. 15 (d,1H) ; MH+ 466· Example 186 5_Fluoro-N_[1-[(1-methyl-4-hexahydropyridinyl)-m-yl]-Hexahydropyridyl]_4_(2-methyl -3_丙·2-基_味峻-4-yl), bit-2-amine at ambient temperature, 5-fluoro+(2-mercapto-3-propan-2-yl-isoxazole- 4-yl)-N-[l-(4-hexahydropyridylsulfonyl)hexahydropyridinyl]-l-pyridine-2-amine (Example 185; 70 mg) and formaldehyde (37% in water, 60 mg) Stir in MeOH (1 ml). Add sodium cyanoborohydride (1M solution in THF, 0. 3 ml) was stirred for 1 hour and then the solvent was evaporated. The residue was diluted with 2M NaOH and extracted with DCM. The combined extracts were washed with brine and concentrated in vacuo. Purification by RPHPLC gave the title compound (m. NMR (400. 13 MHz, CDC13) 1. 55 (m, 8H), 1. 80-2. 00 (m, 4H), 2. 10 (m, 4H), 2. 28 (s,3H),2·60 (s,3H),2·9〇 (m,1H),2·97 (m,2H), 3. 08 (m, 2H), 3. 81 (m5 2H), 3. 90 (m, 1H), 4_88 (d, 1H), 5·50 (m, 1H), 7. 52 (d5 1H)? 8. 15 (d? 1H) ; MH+ 480.  120858 -134· 200811169 Example 187 5_Fluoro-4_(2-indolyl-3-propan-2-yl--oxazol-4-yl) good [1-[(1-prop-2-yl-4) Hexahydropyridyl)-indenyl]-4-hexahydropyridinyl]pyrimidineamine 5-fluoro-4-(2-methyl-3-propan-2-yl-isoxazole ice-based at ambient temperature )-N-[l-(4-hexahydrop to α-defined thiol) winter hexahydroquinone sigma]. The hydrazine 1 amine (Example 185; 70 gram) was stirred with acetone (35 mg) in MeOH (1 mL). Add sodium cyanoborohydride (1M solution in THF, 〇. 3 ml) and stirred for 16 hours. Concentrated HC1 (diluted in MeOH) was added dropwise to adjust the pH to 6, then additional acetone (2 mg) and sodium cyanoborohydride (1 M solution in THF, 0. 3 ml), and the mixture was stirred for 3 hours. The residue was then diluted with 2M NaOH and extracted with DCM. The combined extracts were washed with EtOAc EtOAc m. NMR (400. 13 MHz, CDC13) 1·03 (d, 6H), 1. 55 (m, 8H), 1. 80 (m, 2H), 2. 10 (m, 6H), 2. 60 (s, 3H), 2. 74 (m, 1H), 2. 87 (m5 1H), 2. 98 (m5 2H), 3. 07 (m, 1H), 3. 80 (m, 2H), 3. 90 (m, 1H), 4. 90 (m, 1H), 5·50 (s, 1H), 7. 52 (d, 1H), 8. 15 (d, 1H) ; MH+ 508.  Example 188 6-[[5-Fluoro-4·(2-methyl_3-prop-2-yl)-negative 4-yl), -2-amino]amino]_(1 a,5 a, 6 a) each benzylbicyclo[3丄0]hexane-3-carboxylic acid benzyl ester 2-yl-5-yl-4-(2-methyl-3-propan-2-yl- Taste. Sit-4-yl) cancer sigma (method 8; 53 g) stirred and at (125 ° C) with (la, 5a, 6a)-6-amino-3-nitrobicyclo[3. 1. 0] hexane-3-carboxylic acid decyl ester (preparation 2 in W097/19942; 54 grams) and DIPEA (0. 93 g) was heated together in DMA (12 ml) for 10 hours. The mixture was concentrated by evaporation, then diluted with 2M aqueous sodium carbonate and extracted with DCM. The extract was purified by flash chromatography on EtOAc (EtOAc) elute NMR 1. 42 (d, 6H), 1. 77 (m, 2H), 2. 49 (s, 3H), 3. 46 (m, 2H), 3. 61 (m, 2H), 5. 06 (m, 2H), 5. 50 (m, 1H), 7. 40 (m, 7H), 8. 36 (d, 1H); MH+ 451.  Example 189 N-[5-Fluoro-4-(2·indolyl_3-propan-2-yl-imidazolyl-4-yl)pyrimidin-2-yl]-(1 α,5 α, 6 α )_3 _Nitrobicyclo[3·1·0]hexane-6-amine makes 6-[[5-fluoro-based ice (2·methyl-propanyl- 1 -isoxazole ice-based) mouth in EtOH (36 ml) Acridine-2-yl]amino; ΚΙ α,5 a,6 a )-3-azabicyclo[3丄0]hexane-3_carboxylic acid benzyl ester (Example 18L 72〇 mg), at 10% Hydrogenation was carried out for 2 hours at 1 atm and 40 C in the presence of Pd/c (3 mg). The catalyst was filtered through celite, and the filtrate was evaporated to give the title compound (5 mg, 98%). (400. 13 MHz5 CDC13+ D20) 1. 60 (m, 8H), 2. 60 (m, 4H), 2. 95 (d5 2H)? 3. 15 (d? 2H)5 5. 56 (m, 1H)? 7. 52 (d5 1H)? 8. 16 (d5 1H) ; MH+ 317.  Example 190 Ν·[5-Fluoro.4_(2-methyl-3-propan-2-yl-isoxazole-4-yl)pyrimidinyl]yl]methylsulfonyl-(1 a,5 a; , 6 a ) -3 -azabicyclo[3丄〇]hexane, each amine makes N-[5_fluorobase (2-methyl-3-propyl-propionyl-isoxazole) pyrimidine winter base] (1,5,6α,6α)-3-Azabicyclo[3丄0]hexane-6 amine (Example 189; still mg, 〇2 ι mmol) dissolved in DCM (2 mL). Add chlorinated methane sulfonate (〇〇25 ml, 〇. 32 millimoles), then TEA (〇. 〇 6 ml, 〇 42 mmol, and the mixture was spoiled at ambient temperature for 16 hours. The solvent was evaporated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj NMR (400. 132 MHz) 1. 56 (d, 6H), 1. 87 (s, 2H), 2·56 (s, 3H), 2. 81 (s, 1H), 2. 96 (s, 3H), 3·46 (m, 4H), 5·6〇 (m, 1H), 7. 40 (s, 1H), 7·45 (s, 1H), 8. 43 (s, 1H) ; MH+ 395.  Examples 191 to 193 The following examples were carried out in a manner similar to that of Example 139, and utilized N [5-m-[rho]-[&lt;&quot;&gt; Bite-2-yl]-(1 α,5 (2,bicyclo and 3丄〇1 hexane-6-amine (Example 189) was prepared with the appropriate amine. Example compound π 甶 肌 NMR (400. 132 MHz, CDC13) m/z 191 gas-based 4-(2-mercapto-3-propan-2-yl-flavor σ--4-yl) mouth &amp;, °-2-yl]-3- (2- 4-year old pyrrol-1-ylethylsulfonyl)-(1 α,5 α,6α)-3-azabicyclo[3. 1. 0] Hexane-6-amine 1. 56 (d, 6H), 1. 78 (m, 6H), 2·53 (m, 4H), 2·59 (s, 3H), 2. 82 (d, 1H), 2·91 (t, 3H), 3. 18 (t, 2H), 3. 48 (m, 2H), 3. 73 (d, 2H), 5. 07 (d, 1H), 5. 55 (m5 1H), 7. 54 (d, 1H),8·17 (d,1H) 478 192 3-(2-diamidoethylsulfonyl&gt;N_[5-fluoro-4-(2-methyl-3-) Prop-2-yl-flavor σ sitting·4_yl) σ 唆-2-yl]-(1(2,5〇:,6(3:)-3-nitrobicyclo[3. 1. 0] Hexane-6-amine 1. 56 (d, 6H), 1. 77 (s, 2H), 2. 26 (s, 6H), 2. 59 (s, 3H), 2. 76 (m, 2H), 2·83 (d, 1H), 3. 13 (m, 2H), 3. 46 (m, 2H), 3. 73 (d, 2H), 5. 09 (d, 1H), 5. 55 (m, 1H), 7. 54 (d, 1H), 8. 17 (d,1H) 452 193 3-[2-(7-Azabicyclo[2. 2. 1]hept-7-yl)ethylsulfonyl]-indole-[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-ylmerin-2-yl) ]-(1 α,5α,6α)-3-nitrobicyclo[3. 1. 0] Hexane-6-amine 1. 32 (m, 4H), 1.56 (d, 6H), 1. 72 (m, 6H), 2·59 (s, 3H), 2. 79 (m, 2H), 2. 84 (d, 1H), 3. 14 (m, 2H), 3. 25 (m, 2H), 3. 49 (m, 2H), 3. 72 (d, 2H), 5. 08 (d, 1H), 5·55 (m, 1H), 7. 54 (d, 2H), 8. 17 (d, 2H) 504 120858 -137- 200811169 Example 194 N-[5-Fluoro-4-(2-methyl-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]-3 -(3-tetrahydropylo-1-ylpropylsulfonyl)_(1 α,5 α,6 α )_3_azabicyclo[3. 1. 0] Hexane-6-amine gives Ν-[5-carbyl-4-(2-methyl-3-propan-2-yl-flavor α-spin-4-yl)u-succinyl-2-yl] -(1 〇;, 5 α,6 a )-3-azabicyclo[3·1·〇]hexa-6-amine (Example 189; 285 mg) and DIPEA (349 mg) dissolved in DCM (15 ml) ) and cooled to _1 〇. Hey. Then 3-chloropropane sulfonium chloride (176 mg) in DCM (2 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min then evaporated to dryness. The residue was dissolved in DMF (6 mL) and taken to EtOAc. DIPEA (39 mg) and tetrahydropyrrole (300 mg) were added to one portion, and the reaction mixture was heated at 70 ° C for 16 hours. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc NMR (400. 13 MHz, CDC13) 1. 57 (d, 6H), 1·80 (m, 6H), 2. 00 (m, 2H), 2. 55 (m, 9H), 2·83 (d, 1H), 3. 05 (m, 2H), 3. 46 (m, 2H), 3. 72 (d, 2H), 5. 08 (d, 1H), 5. 57 (m, 1H), 7. 54 (d, 1H), 8. 17 (d, 1H) ; MH+ 492.  Examples 195 to 199 The following compounds were prepared by the procedure of Example 194 and using the remaining liquids and the appropriate amines on the same scale. Example Compound NMR (400. 132 MHz, CDC13) m/z 195 N-[5-fluoro-4-(2-methyl-3-propan-2-yl-11 m嗤-4-yl) sneeze-2·yl]-3 -[3-(l-hexahydro outside 1: dimethyl)propyl thiol]-(1 〇:,5〇:,6〇:)-3-azabicyclo[3·1·0]hexane -6-amine 1. 43 (m, 2H), 1. 55 (m, 10H), 1. 78 (m, 2H), 1. 97 (m, 2H), 2. 36 (m, 6H), 2. 59 (s, 3H), 2. 83 (d, 1H), 3. 02 (m, 2H), 3. 47 (m, 2H), 3. 72 (d, 2H), 5·09 (d, 1H), 5. 57 (m, 1H), 7. 54 (d,1H), 8·17 (d,1H) 506 120858 -138 - 200811169 196 3-[3-(N-Cyclopentyl-N-methyl-amino)propyl continuation]-Ν -[5-fluoro-4-(2-methyl-3-propan-2-yl-flavor β-sodium-4-yl)- phen-2-yl]-(1 α, 5α, 6α)-3_ Nitrobicyclo[3·1·0]hexane-6-amine # 520 197 3-[3-(2,5-Dimethyltetrahydropyranyl-1-yl)propyl continuation]-Ν -[5-Fluoro-4_(2-methyl_3_propan-2-yl-flavor. sit-4-yl)pyrimidin-2-yl]-(1α, 5α,6α)-3_azabicyclo [3. 1. 0]Heat--6-amine #520 198 3-(3-Dimethylaminopropylsulfonyl)-N-[5-fluoro-4-(2-methyl-3-prop-2-yl) -Mimi-4-yl&gt;Milybdo-2-yl]-(1«,5〇:,6〇;)-3-Azabicyclo[3. 1. 0]hexane-6-amine* 1. 58 (d, 6Η), 1. 77 (s, 2Η), 1. 96 (m, 2H), 2. 21 (s, 6H), 2. 37 (t, 2H), 2. 59 (s, 3H), 2·83 (d, 1H), 3. 02 (m, 2H), 3·48 (m, 2H), 3. 73 (m, 2H), 5. 08 (d,1H), 5_56 (m,1H),7·54 (d,1H), 8·17 (d,1H) 466 199 3-|&gt;(7-nitrobicyclo[2. 2. 1]hept-7-yl)propylsulfonyl]_Ν-[5·fluoro-4-(2-methyl-3-propan-2-yl-flavor-4-yl)♦ °-2 -yl]-(1 α,5α,6α)·3·azabicyclo[3. 1. 0]Heat--6-amine # 1. 29 (m, 4H), 1·60 (d, 6H), 1. 71 (m, 4H), 1. 79 (s, 2H), 1.97 (m, 2H), 2. 47 (t, 2H), 2. 59 (s, 3H), 2. 83 (d, 1H), 3. 11 (m, 2H), 3. 26 (s, 2H), 3. 46 (m, 2H), 3. 73 (d, 2H), 5. 08 (d, 1H), 5. 56 (m, 1H), 7·54 (d, 1H), 8. 17 (d, 1H) 518 was carried out at ambient temperature for 7 days # at 95 ° C for 2 days Example 200 4-[[4-(3-cyclopentyl-2-methyl-miso-4-yl) -5-fluoro-mouth-2-yl]amino]', nitrogen p-pyridyl carboxylic acid benzyl ester (E)-l-(3_cyclopentyl-2-mercapto-isoxazole) _3_dimethylamino-propene; ene small 120858-139- 200811169 ketone (method 13; 6 7 夯, 27 1 stalk and, 、 丄 丄 u u brother · i pen 旲 ear) added to anhydrous acetonitrile ( 14 〇 ml) and cooled to -2 C, then add SelectfluorTM (12 g, 33. 9 mmol), keeping the temperature at _2 °C. Next, the reaction was allowed to warm to ambient temperature and stirred for 30 minutes and then evaporated to dryness. A saturated aqueous solution of NaHc.sub.3 was added, then aqueous layer was extracted with DCM (3.times. Adding the gum to the 'aminocarbimine guanamine hexahydropyridine carboxylic acid oxime ester (Method 14; 8.2 g, 29.8 mmol) to 2-methoxyethanol (1 〇〇 ml) Medium and heated under reflux for 16 hours. The reaction was then evaporated to dryness and a saturated aqueous NaHCO3 solution was added, followed by extraction with DCM (3.times.150 mL), dehydration, and solvent was removed in vacuo to yield a viscous black oil. Purification by flash chromatography on silica gel eluted with 0-5% MeOH in DCM to afford a solid that was dissolved in DCM &lt;&quot;&quot;&quot;&quot; . The precipitate was filtered and dried <RTI ID=0.0> NMR (400. 132 MHz, CDC13) 1. 40-1. 48 (m, 2H), 1. 62-1. 73 (m, 2H), 1. 88-2. 05 (m, 6H), 2. 11-2. 19 (m, 2H), 2. 57 (s, 3H), 2. 97-3. 03 (m, 2H), 3. 85-3. 94 (m, 1H), 4. 14 (d, 2H), 4·90 (d, 1H), 5. 14 (s, 2H), 5. 57-5. 62 (m, 1H), 7. 29-7. 37 (m, 5H), 7. 51 (d, 1H), 8. 15 (d,1H) ; MH+ 479· Example 201 4-(3-Cyclopentyl-2-methyl-Nan-4-yl)-5-fluoro-indole·(4-hexahydroindenyl), Bitrate the amine in 40 ° C and 5 bar of hydrogen, 4-[[4-(3- 哀 戊 基 -2- -2-methyl- miso _4_ base)·5 in EtOH (100 ml) -Fluoro-spray sigma-2-yl]amino] hexahydro-P is a bitter sulphate (example 200; 4. 5 grams, 11. 3 millimoles) with 10% Pd/C (0. 45 g) stirred for 16 hours. The reaction mixture was filtered through a pad of Celite, and solvent was removed, 120858 - 140 - 200811169 to give a waxy solid. Pass it through the short 矽 hose column, in the DCM. 5-10% MeOH was dissolved. The obtained gum was recrystallized from hot acetonitrile to give the title compound. NMR (400. 132 MHz, CDC13) 1. 41 (ddd, 2H), 1. 65-1. 72 (m, 2H), 1. 89-2. 05 (m, 6H), 2. 11-2. 21 (m, 2H), 2·58 (s, 3H), 2. 67-2. 74 (m, 2H), 3. 11-3. 14 (m, 2H), 3. 77-3. 86 (m, 1H), 4. 94 (d, 1H), 5. 61-5. 73 (m, 1H), 7. 51 (d, 1H), 8. 14 (d, 1H) ; MH+ 345.  Example 202 4-(3-Cyclopentyl-2-methyl-isobenzo-4-yl)-5-fluoro-N-(l-methyl-an-yl-4-hexahydropyridinyl)pyrimidine- The 2-amine title compound was used in a similar manner to Example 115 and used in a similar scale using 4-(3- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; - hexanitrogen p is sigma-based) u-sigmine amine (Example 201) is prepared as a starting material. NMR (400. 132 ΜΗζ, CDC13) 1. 6M. 73 (m5 4H)? 1. 89-2. 08 (m5 4H), 2. 13-2. 17 (m? 4H)? 2. 58 (s, 3H), 2. 81 (s, 3H), 2. 91 (dt, 2H), 3. 74-3. 77 (m5 2H), 3. 83-3. 92 (m, 1H), 4. 98 (d, 1H), 5. 53 (Five peaks, 1H), 7. 51 (d, 1H), 8. 16 (d, 1H) ; MH+ 423.  Examples 203 to 204 The following examples were carried out in a similar manner to Example 139, using 4-(3-cyclopentyl-2-methyl-imidazol-4-yl) 5-fluoro K4-hexahydropyridine on a similar scale. The pyrimidine-2-amine (Example 201) was prepared as a starting material. 120858 -141- 200811169 Examples Compound NMR (400. 132 MHz, CDC13) m/z 203 4-(3-ίchen-decyl-2-methyl-imidazol-4-yl)-5-fluoro-N-[l-(2-tetrazo-p-bi-l-1 -ethylethyl sulphate)-4-hexahydroexidinyl]pyrimidin-2-amine 1. 57-1. 72 (m, 4H), 1. 79-1. 83 (m, 4H), 1. 85-2. 19 (m, 8H), 2. 54-2. 58 (m, 7H), 2. 90-3. 02 (m, 4H), 3. 14-3. 18 (m, 2H), 3. 76-3. 79 (m, 2H), 3. 83-3. 92 (m, 1H), 4. 93 (d, 1H), 5·53 (Wufeng, 1H), 7. 50 (d5 1H), 8. 16 (d,1H) 506 204 4_(3_Cyclopentyl-2-methyl-imidazol-4-yl)-N-[l-(2-dimethylaminoethylsulfonyl)-4-hexa Hydropyridyl]-5-fluoromethane-2-amine 1. 57-1. 70 (m, 4H), 1. 88-2. 19 (m, 8H), 2. 28 (s, 6H), 2. 58 (s, 3H)? 2. 76 (t? 2H) 5 2. 96-3. 02 (m5 2H), 3. 10 (t, 2H), 3. 76-3. 79 (m, 2H), 3. 85-3. 94 (m, 1H), 4. 96 (d, 1H), 5. 54 (Five peaks, 1H), 7. 50 (d, 1H), 8. 16 (d,1H) 480 Example 205 N-[l-(3-Actylpropyl-decyl)-4_hexahydroindole]-4-(3-cyclopentyl-2-methyl-imidazole 4--4-)-5-fluoro-pyrimidine-2-amine The title compound was obtained in a similar manner to Example 143, and using 4-(3-cyclopentyl-2.methyl-flavor ))-5·Fluoro-N-(4-hexahydrogen: 1. benzyl) aceton-2-amine (Example 2〇1) was prepared as a starting material. MH+ 487.  Examples 206 to 207 The following compounds were obtained by the procedure of Example 144 and using N-[l-(3-chloropropylsulfonyl) hexahydropyridyl] ice (3-cyclopentyl) on the same scale. !] -Imidazole-4-yl)-5H sec-2-amine (Example 205) was prepared with the appropriate amine. 120858 142- 200811169 Examples Compound NMR (400. 132 MHz, CDC13) m/z 206 4-(3-cyclopentyl-2-methyl-imidazol-4-yl)·indole-[1-(3-dimethylaminopropylsulfonyl)-4 - hexanitrozinium ratio sigma]-5-fluoro-pyrimidin-2-amine 1. 57-1. 72 (m, 4H) 5 1. 92-2. 17 (m, 10H), 2·22 (s, 6H), 2. 39 (t5 2H), 2. 58 (s, 3H), 2. 95-3. 02 (m, 4H) 5 3. 77 (d5 2H)? 3. 83-3. 92 (m, 1H), 5. 01 (d, 1H), 5. 54 (Wufeng, 1H), 7. 50 (d,1H), 8_16 (d,1H) 494 ^ 207 4-(3-ί戍戍-2-methyl_imidazol-4-yl)-5-fluoro-Ν-[1-(3- Tetrahydropyrrole-1-ylpropyl sulphate)-4-hexapyridinylpyrimidin-2-amine 1. 62-1. 74 (m, 4H), 1. 89-2. 19 (m, 12H), 2. 30 (five peaks, 2H), 2. 57 (s, 3H) 5 3. 01-3. 09 (m5 8H)? 3. 20 (t, 2H), 3·76_3·80 (m, 2H), 3. 86-3. 95 (m, 1H), 5·21 (d, 1H), 5·54 (five peaks, 1H), 7. 49 (d, 1H), 8. 15 (d,1H) 520 ^ Example 208 3-[[5-Arsyl.4_(2-Methyl_3_propan-2-yl-imidazolyl), pyridine:yl]aminopyrazine Small carboxylic acid tert-butyl ester 3-aminocarbimimine guanamine-nitrosopenoxane small carboxylic acid tert-butyl ester (Method 15 ·, 192 mg, 〇. 75 millimoles) with (2) 3_(dimethylaminofluoro-indolyl-7-isopropyl-2-methyl-1indole-imidazol-5-yl)prop-2-en-1-one (at W007015064) Method 1) (360 mg, L50 mmol) in 2-methoxyethanol (1 mL) was heated under reflux for 24 hours. The solvent was then evaporated and the residue was taken on a silica gel. Purification by chromatography, eluting with EtOAc-EtOAc (EtOAc) Nmr (shed 丨^ should ^, CDC13) 1. 43 (m? 16H)5 1. 65 (m5 4H)5 1. 92 (m5 1H) 5 2. 52 (s? 3H)? 3. 06 (m, 1H), 3. 39 (m, 1H), 3·63 (m, 2H), 4. 08 (m, ih), 5·5〇 (m, 1H), 7 19 (s, 1H), 7. 44 (d, 1H), 8. 06 (s,ih) ; m/Z433.  Example 209 Ν·[5-Fluoro-4-(2-amilyl-propionyl-azyl yl)pyrimidin-2-yl]-nitrogen sulphide 120858-143 .  200811169 Alkyl-3-amine added trifluoroacetic acid (〇·5 ml) to 3-[[5-fluoro-based (2-methyl-propionyl-isoxyl-4-yl)pyrimidine at ambient temperature Each group]amino]nitros-7-decane+carboxylic acid tert-butyl ester (Example 2〇8; 48 mg, 0. 11 Moel) in DCM (1. 0 ml) in the stirred solution. 2. After 5 hours, the solvent was evaporated to give crystalljjjjjjjjj M/z 333· Example 210 义[5_Fluoro-4-(2-methyl-1-prop-2-yl------------------------------------------------ Nitrogen and heptasulfuric acid-3-amine will be gasified and burned in the S temperature basket at the soil temperature (0. 013 ml, 〇17 mmol) with triethylamine (0. 046 ml, 0. 33 mmoles) added to N_[5_Fluoro-based (2-methyl-3-propan-2-yl-isoxazolyl) hydrazinyl]-nitrogen sulfonium each amine (Example 2〇9; 1 〇3 耄)) in a stirred solution in DCM (2 house liters). After 4 hours, another cesium chloride sulfonate was added (0. 013 ml, 0. 17 mmoles and the reaction mixture was stirred at ambient temperature for 64 hours. The solvent was evaporated to give a gum which was dissolved in MeOH and loaded on a SCX-2 column. The column was washed three times with Me 〇 H and then dissolved in 2M NHs / MeOH. The title compound was obtained as a colorless solid (7 mg, 16%). _ (4〇〇132 MHz, MeOH) 1. 65 (d5 6H), 1. 82 (m, 6H), 2. G3 (m, 2H), 2_81 (s, 3H), 2. 87 (s, 3H), 3·38 (m, 4H), 4. 16 (m, 1H), 5. 53 (m, 1H), 7.84 (s, 1H), 8. 40 (s, 1H) ; m/z 411.  Method for the preparation of starting materials 1 4-Aminocarbimine decylamine hexahydroindole small sulphuric acid vinegar 120858 -144 - 200811169 Benzyl 4-aminopyropyridine carboxylic acid (25 g, ι〇) 6·7 millimolar), pyrazole•1-rebel imine amide (31. 3 grams, 213. 4 mmoles and TEA (30 ml) were dissolved in MeCN (500 mL) and heated at 60 ° C overnight. After 18 hours, the solvent was evaporated. The resulting orange residue was partitioned between saturated aqueous NaHC3 (5 mL) and DCM (500 mL). The dcm layer was separated, and the fine precipitate contained therein was collected by a transition, and then washed with a small amount of DCM and dried under vacuum to give a white solid (3 〇 8 g, 1%). Nmr (400. 132 MHz) 1. 31 (m, 2H), 1. 82 (m, 2H), 2·96 (m, 2H), 3. 57 (m, 1H), 3·92 (m, 2H), 5. 08 (s5 2H), 7·35 (m, 5H), 7. 96 (s, 2H)_ Method 2 Aminocarbinimine oxime amide tetrahydropyrrole carboxylic acid tert-butyl ester in 3-aminotetrahydropyrrole carboxylic acid tert-butyl ester (3 〇 3 g, 16.27 millimolar) In a solution of acetonitrile (60 house liters), add ΤΕΑ (4·7 ml, 32 75 mmol), followed by 111 峨嗤 竣 small 竣 脒 hydrochloride (4· 8 grams, 33. 72 millimoles). The reaction mixture was heated to 65 ° C (internal temperature) for 6 hours and then left to cool overnight. The reaction mixture was evaporated to give a viscous oil with squid pink, which was partitioned between saturated aqueous NaHC 3 (75 mL) and DCM (7 mL). Next, the mixture was vigorously shaken, and allowed to stand for 10 minutes, then shaken again, and the formed solid was collected by filtration. The filter cake was washed with DCM, water and dried under suction for </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; %). NMR (400. 132 MHz) M1 (s, 9H), 1. 78 (m, 1Η), 2·09 (m, 1H), 3. 07 (m, 1H), 3. 15-3. 51 (m, 4H), 4·03 (m, 1H), 7. 01-8. 81 (m, 3H)· 120858 -145· 200811169 Method 3 4-Fofolin-4-ylbutyrate hydrochloride Add ethyl 4-bromobutyrate (67 ml, 〇·5Μ) dropwise? Fuline (175 liters, 2 Torr) in a solution of anhydrous toluene (1 liter). The reaction mixture was stirred at 60 ° C for 4 hours and then at ambient temperature for 16 hours. Next, the reaction mixture was filtered&apos; and the filtrate was evaporated. The formed material was developed with 6〇-8〇 light oil and evaporated to obtain an orange oil (91. 4 g), which was distilled under reduced pressure to obtain a transparent oil (73. 2 g), boiling point 90 · 2 ΐ / 3-4 mm Hg. The resulting oil was heated under reflux for 18 hours in 18% HCl (aq) (1 liter). The acid was evaporated to give a white solid (75. 43 g, 53%), melting point 181-3 ° C. Method 4 4-(2-Mercapto-3-propan-2-yl-pyridin-4-yl) cough-2 alcohol in an inert atmosphere to give 4-(2-methyl-propionyl-isazole Bucketin, cimetidine (Method 39, WO 2003/076436, 5 g, 23 mmol) was dissolved in 70% AcOH_water (145 mL). Add sodium nitrite in water (1 () ml) at ambient temperature (5. 52 grams, 80 millimoles), resulting in a mild exotherm over a 5 minute period. The reaction mixture was slowly heated to 60 ° C and maintained at this temperature for 3 hours. The reaction mixture was cooled to mp EtOAc (EtOAc m. (8. 2 grams 43%). NMR (400. 132 MHz, CDC13) 1. 51 (d, 6H), 2. 03 (s, 3H), 2. 54 (s, 3H), 5. 93 (m, 1H), 6. 60 (d, 1H), 7. 57 (m, 2H) ; MH+ 219.  120858 -146- 200811169 Method 5 2-Alkyl-4-(2-methyl-3-propan-2-yl-miso-4-yl) smear 4-(2-mercapto-3-propyl- 2-yl-pyran-4-yl) spray π-den-2-ol (Method 4; 8. 2 grams, 29. 4 mM), bismuth chloride (120 ml) and phosphorus pentachloride (6. 6 g) were combined under reflux heating for 18 hours. Excess palladium chloride was evaporated and the residue was dissolved in DCM and stirred with ice and water. The mixture was brought to pH η by adding a 4% aqueous solution of sodium hydroxide. The organic material was separated from the aqueous phase and the organic phase was washed with brine, dried and dried. The resulting material was dissolved in DCM and chromatographed on silica gel eluting on a gradient gradient of &lt;RTIgt; The title compound was obtained as a pale brown gum (5·8 g, 84%). ^^(4〇〇132乂他) 1·53 (d,6Η), 2. 50 (s, 3Η), 5. 27 (m, 1Η), 7. 72 (s, 1Η), 7·79 (d, 1Η), 8. 62 (d, 1H) ; MH+ 237.  Method 6 2,5_一气-4_(2-methyl_3_propyl:yl-isoxazole_4_yl) acetonidine to give 5-alkyl-4-(2-methylpropyl-isoxazole ice-based) Pyrimidine-2-amine (Method 5, j W005/075461 towel, 5 g, 19 9 mmol) dissolved in acetic acid (7) ml) / water (3 〇: liter) and slowly added water (8 ml) Sodium nitrite (2. 75 grams, 39. 8 millimoles). The reaction was stirred at ambient temperature for 1 min, then at 6 (TC ..., 3 h. then the reaction was evaporated to dryness, NaHC03 W &lt;0&gt;&gt; to &lt;RTI ID=0.0&gt; The combined organic matter is dehydrated, dried, selected, β, filtered, and the solvent is removed in vacuo to obtain a solid which is dissolved in a minimum amount of 7 liters of hot acetonitrile. Upon cooling, a white solid is obtained. Add the solid to the emulsified phosphatium phosphate (50 t liter) and heat at 120 ° C for 1 120858 • 147 - 200811169 hours. Allow the reaction mixture to evaporate to dryness, then carefully react with saturated aqueous NaHC 3 solution. It was quenched to pH 8. The title compound was crystallised eluted eluted elute 132 MHz, CDC13) 1. 58 (d,6H),2·61 (s,3H),4·96 (seven peaks, 1Η), 7·80 (S,1H), 8. 58 (s,1Η) ; ΜΗ+ 273· Method 7 5-Fluoro-4-(2•fluorenyl-3-propan-2-yl oxazole-4-yl)-chal-2-ol acetate is inert Under the atmosphere, 5-fluoro-4-(2-methyl-3-triprop-2-yl^moxazolidine), pyridin-2-amine (Method 17 in W02006/064251; 4 g, 17 Millol) was dissolved in 70% AcOH_water (108 mL). Add sodium nitrite in water (8 ml) at ambient temperature (4. 08 grams, 59. 2 millimoles), after 5 minutes. The reaction mixture was slowly warmed to 60 °C. After 3 hours, the reaction mixture was cooled and then neutralized to pH 7 with a 40% aqueous NaOH solution. The aqueous layer was extracted with EtOAc (EtOAc EtOAc. 07 grams, 81%). NMR (400. 132 MHz) 1. 48 (d,6H),1·91 (s,3H),2·50 (s,3H),5. 44 (m, 1H), 7. 47 (d, 1H), 8. 29 (d? 1H) ; MH+ 237.  Method 8 2-Alkyl-5·fluoro-4-(2-mercapto-3·propan-2-yl-miso-4_yl), biting 5-fluoroyl ice (2-methyl-3-) Prop-2-yl-imidazol-4-yl)pyrimidin-2-ol acetate (Method 7; 4 g, 13. 5 mmoles suspended in bismuth chloride (25 ml) and heated to 90 ° C for 3. 5 hours. The reaction mixture was concentrated with EtOAc EtOAc m. The mixture was cooled in an ice-water bath and neutralized to pH 8 with a 40% aqueous NaOH solution of 120 s s s s s s s s s s s s s s s s s s s s The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. Purification by flash chromatography on EtOAc EtOAc (EtOAc) elute 84 grams, 83%). NMR (400. 132 MHz, CDC13) 1. 54 (d, 6H), 2. 54 (s, 3H), 5. 34 (m, 1H), 7. 69 (m, 1H), 8. 32 (m, 1H) ; MH+ 255.  Method 9 N-cyclodecyl-5-methyl-l,2-v-indole-4-amine 5-methyl-1,2-oxazol-4-amine hydrochloride (20 g), cyclopentane Ketone (13. 9 ml) and sodium acetate (12. 3 g) was added to MeOH (200 mL) and stirred at 0 ° C for 1 hour. Slowly add NaCNBH3 (11. 5 g), after 20 minutes while keeping the temperature below 0 °C. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred for 16 h then solvent was evaporated in vacuo. The solid obtained was dissolved in saturated aqueous NH.sub.4Cl (1 mL) and extracted with ether (2.times. The combined organic extracts were dried <RTI ID=0.0>: </RTI> <RTI ID=0.0> The oil was purified by column chromatography on silica gel using 1 〇5 〇〇 /0 ether in isohexane as the solvent. The solvent was removed in vacuo to give the title compound as a yellow oil (17.2 g). NMR (300. 072 MHz, CDC13) 1. 37-1. 47 (m, 2Η), 1. 54-1. 79 (m5 4Η), 1·83-1·94 (m, 2H), 2. 31 (s, 3H), 3·51 (five peaks, 1H), 8. 03 (s5 1H); m/zl67·method 10 N-cyclopentyl_N-(5-methyl-1,2-oxazol-4-yl)acetamide to acetic anhydride (18·9 ml) Addition to N-cyclopentyl-5-mercapto-1,2-carbazole 120858-149- 200811169 Amine (Method 9 '16·〇克) in a solution of acetic acid (1 mM) After 20 minutes. After 1 hour, the solvent was removed in vacuo and the resulting syrup was treated with aqueous K.sub.2CO.sub.3 (50 mL, mp. The aqueous layer was extracted with hydrazine (3 X 50 liters), and the combined organic material was dried (n^s 〇 4) and the solvent was removed in vacuo. The solid obtained was dried under high vacuum to give the title compound as a yellow solid (19. 0 g). NMR (300. 074 MHz) 1. 08-1. 24 (m, 2H)? 1. 4M. 51 (m, 4H)? 1. 69 (s5 3H), 1. 74-1. 80 (m5 2H) 5 2. 33 (s, 3H), 4_77 (five peaks, ih), 8·64 (s, 1H); MH+ 209.  Method 11 N-[(E)-1-Amino-3-carboxylate·butyl succinyl-2-yl] with cyclopentyl-acetamide N-cyclopentyl_N-(5-f- Isoindazol) acetamide (method 1 〇; 19 g, 913⁄4 mol) and 1 〇 palladium/carbon gram), under hydrogen atmosphere, at elevated pressure (4 atm) in EtOH Stir. The reaction was then filtered and the solvent was removed in vacuo. The title compound was obtained as a colorless solid (16 g, 84%). NMR (300. 074 MHz) 1. 19-1. 49 (m? 6H), 1. 59-1. 80 (m5 5H)? 2. 06 (s5 3H), 4·44 (Wufeng, 1H), 6. 84 (d, 2H), 7. 59 (t, 1H) ; MH+ 211.  Method 12 1_(3-Cyclodecyl 2 -methyl-miso-4-yl)ethanone N-[(E)-1-amino-3-keto-buten-2-yl] -N-cyclopentyl-acetamide (Method 11; 16. 0 g) with NaOH (3. 66 g) was added to EtOH (200 mL) and heated under reflux for 4 hr. Add NI^Cl (6. 11 g), and the mixture was stirred at ambient temperature for 16 hours and then concentrated in vacuo. Ether (35 Torr) was added and the mixture was stirred for 10 min then filtered and concentrated in vacuo. 120858 -150- 200811169 The yellow oil obtained was distilled under reduced pressure (0·55 mbar / 1 Torr (rc) to give the title compound as a transparent oil (10.08 g). Lihan (4〇〇132) MHz, cdC13) 1. 66-1. 71 (m, 2H), 1. 97-2. 04 (m, 6H), 2·45 (s, 3H), 2. 50 (s, 3H), 5.22 (five peaks, 1H), 7. 73 (s,1H) ; MH+ 193 · Method 13 (E)-l_(3-cyclopentyl-2-methylzole azole) each dimethylamino-propan-2- ketone will be 1·( 3-cyclopentyl-2-methyl-oxazol-4-yl)ethanone (Method 12; 10. 08 g) and DMF-DMA (17. 9 ml) was added to DMF (150 ml) and heated at 130 ° C for ό hours. The solvent was removed in vacuo and dcm (10 mL) was added followed by a scale (100 mL). The mixture was sonicated for 1 min, then filtered and dried to give the title compound as a yellow solid. 74 grams). NMR (400. 132 ΜΗζ, CDC13) 1. 61-1. 72 (m, 2Η), 1. 91-2. 14 (m, 6Η), 2·49 (s, 3Η), 2·99 (s, 6Η), 5. 35 (Wufeng, 1Η), 5.52 (d, 1Η), 7·48 (s, 1Η), 7.62 (d, 1Η); ΜΗ+ 248.  Method 14 4-Amino-based imine amide-amine hexahydro-u is more suitable for the 4-amino hexahydro-p-pyrene-1-weilic acid g (2 gram, 85. 5 mM) and TEA (24 ml, 171 mmol) dissolved in acetonitrile (300 mL), then m_ 咐嗤 small carboxamide (25 g, 171 mmol) and the reaction at 65t Heat down for 16 hours. The reaction mixture was evaporated to dryness EtOAcqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH An orange solid is produced. A gambling (100 ml) was added and the residue was taken at 65 ° C; the resulting syrup was cooled and filtered to give the title compound as a colourless solid. NMR (400. 132 MHz) 1. 27-1. 36 (m, 2H), 1. 81-1. 83 (m, 120858 -151 - 200811169 2H), 3·18-3·55 (m, 3H), 3. 93 (d, 2H), 5. 08 (s, 2H), 7. 30-7. 41 (m, 5H), 7. 60-8. 55 (brs, 4H) ; MH+ 277 Method 15 3-Aminocarbinimine oxime-nitrogen-7gn-slow-acid acid-single-acetic acid pyrazole-1-carboxyindoleimine hydrochloride (739 mg , 5 〇 4 mM) was added to the amino-amine heptadecane + carboxylic acid tri-butyl ester (541 mg, 2. 52 mmol) and diethylamine (0. 7 ml, 5·04 mmoles of this compound was heated under reflux in a mixture of acetonitrile (15 ml). After 5 hours, it was cooled to EtOAc (EtOAc)EtOAc. The acetonitrile filtrate was evaporated in vacuo. The obtained gum was dissolved in DCM and saturated aqueous sodium hydrogen carbonate was added and the mixture was left at ambient temperature for 16 hours. The solid was dried and dried <RTI ID=0.0> NMR (400. 132 MHz) 1. 41 (m, 9H), 1. 68 (m, 3H), 3. 37 (m, 8H), 7·81 (s, 2H).  EXAMPLE 211 The following is a representative pharmaceutical dosage form containing a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof (hereinafter compound X), for therapeutic or prophylactic use in humans: - (8): tablets Agent I mg / tablet compound X 100 lactose Ph. Eur 182. 75 burial sodium carboxymethyl cellulose 12. 0 corn starch paste (5% w/v paste) 2. 25 magnesium stearate 3. 0 120858 -152- 200811169 (b): Tablets II mg / tablet Compound X 50 Lactose Ph. Eur 223. 75 croscarmellose sodium 6. 0 corn starch 15. 0 Polyethylene tetrahydroindole ketone (5% w/v paste) 2. 25 magnesium stearate 3. 0 (c): Tablets III mg/tablet Compound X 1. 0 lactose Ph. Eur 93. 25 croscarmellose sodium 4. 0 corn starch paste (5% w/v paste) 0. 75 magnesium stearate 1. 0 (d): capsule mg/capsule Compound X 10 Lactose Ph. Eur 488. 5 magnesium stearate 1. 5 (8): Injection I (50 mg / ml) Compound X 5. 0% w/v 1M sodium hydroxide solution 15. 0% v/v 0. 1M hydrochloric acid (to adjust the pH to 7.6) polyethylene glycol 400 4. 5% w/v water for injection to 100% 120858 -153 - 200811169 (¢): Injection II 10 mg / ml Compound X 1. 0% w/v sodium phosphate BP 3. 6% w/v 0. 1M sodium hydroxide solution 15. 0% v/v water for injection to 100% (g): Injection III (1 mg/ml, buffered to pH 6) Compound X 0. 1% w/v sodium phosphate BP 2. 26% w/v citric acid 0. 38% w/v polyethylene glycol 4〇〇 3. 5% w/v water for injection to 100% Note The above formula can be obtained by customary procedures known in the art of medicine. Tablets (4)-(c) can be coated by enteric materials by conventional means, for example by providing a coating of cellulose acetate S too vinegar. 120858 -154-

Claims (1)

200811169 十、申請專利範圍： 1· 一種式（I)化合物：200811169 X. Patent application scope: 1. A compound of formula (I): 環A為5-7員飽和雜環，其含有一個氮原子與視情況選 用之1或2個其他雜原子，選自N、〇或s;其中環八之2個 原子可視情況被橋基連接； R1為氮上之取代基，且係選自氫、Ci 6烷基、Ci 6烷醯 基、胺甲醯基、N-(C卜6烷基）胺甲醯基、n，n_(Ch烷基）胺甲 醯基、N-(Ci·6烯基）胺甲醯基、Ν,Ν-βυ烯基）胺甲醯基、胺 石黃醯基、烷基）胺磺醯基、N，N_(Ci6烷基胺磺醯基、 N-d6烯基）胺磺醯基、N，N_(Ci-6烯基)2胺磺醯基、Ci 6烷氧 ‘基、Ch烧基續醯基、（^_6烯基續驢基、碳環基-R6或雜 環基-R7 ;其中R1可視情況在碳上被一或多個R8取代；且其 中右$亥雜壞基含有-NH·»部份基團，則該氮可視情況被選自 R9之基團取代； R2為碳上之取代基，且係選自鹵基、硝基、氰基、羥 基、胺基、叛基、胺甲酿基、魏基、胺確酿基、Ci- 6烧基、 C2-6烯基、C2-6炔基、Cb6烷氧基、Ch烷醯基、q-6烷醯 氧基、N-(Ch烷基）胺基、N，N-(Ch烷基)2胺基、C卜6烷醯胺 120858 200811169 基、N-(Ch烷基）胺甲醯基、烷基）2胺曱醯基、Cl_6 烷基S(0)a，其中a為0至2，Cw烷氧羰基、烷基）胺 磺醯基、Ν,Ν-Α _6烷基h胺磺醯基、Ci _6烷基磺醯基胺基、 碳環基-R1G -或雜環基-R11-;其中R2可視情況在碳上被一或 多個R12取代；且其中若該雜環基含有^部份基團，則 該氮可視情況被選自R13之基團取代； q為0-4 ;其中R2之意義可為相同或不同； R3係選自鹵基、氰基或胺基； η為0至2，其中R3之意義可為相同或不同； R4係選自乙基、丙基、異丙基、丁基、異丁基、第二_ 丁基、第三-丁基、環丙基、環丙基甲基、μ環丙基乙基、 環丁基曱基、環戊基或環丁基；其中R4可視情況在碳上被 一或多個R14取代； R5係選自甲基、乙基、異丙基、氟基甲基、二氟甲基、 一氟甲基、甲乳基甲基、壞丙基甲基或環丙基； R6 與 R7 係獨立選自-C(O)-、-C(0)N(R15)-、-S(0)2-或 _S〇2N(R16)-;其中R15與Ri6係獨立選自氫或Ci 6烷基； R8與R12係獨立選自鹵基、硝基、氰基、羥基、胺基、 羧基、胺曱醯基、酼基、胺磺醯基、（^_6烷基、C2_6烯基、 〇2_6炔基、CV6烷氧基、（：卜6烷醯基、Ch烷醯氧基、N-(Ch 燒基）胺基、N，N-(Ch烷基）2胺基、Ch烷醯胺基、n_(Ch 燒基）胺甲醯基、N，N-(Ch烷基)2胺甲醯基、Cu烷基S(0)a， 其中a為0至2，q — 6烷氧羰基、NjCu烷基）胺磺醯基、 ΗΝ·% _6烧基h胺績醯基、q - 6烧基績醯基胺基、礙環基 120858 200811169 _R17-或雜環基-R18-;其中圮與]^2可互相獨立地視情況在 石厌上被一或多個R19取代；且其中若該雜環基含有_顺_部 份基團，則該氮可視情況被選自R2〇之基團取代； r9，r13及r2G係獨立選自Ci-6烷基、Ch烷醯基、〇卜6烷 基磺醯基、Cu烷氧羰基、胺甲醯基、n-(Ci_6烷基）胺甲醯 基、Ν,Ν-Α _6烷基）胺甲醯基、爷基、；氧羰基、苯甲醯基 及苯基磺醯基；其中R9, Ri3及r2〇可互相獨立地視情況在 碳上被一或多個R21取代； Κ10，^1，！^7及R18係獨立選自直接鍵結、·〇_、_N(R2'、 C(O)-、-N(R23)C(0)·、-C(0)N(R24)-、-S(0)s-、-S02N(R25)-或 -N(R26)S02-;其中R22, R23, R24, R25及RM係獨立選自氫或 Ci - 6烧基’且s為0-2 ; R14係選自鹵基、硝基、氰基、羥基、胺基、羧基、胺 甲醯基、魏基、胺確醯基、Ci_6烧氧基、C^-6烧醢基、Cu 烷醯氧基、Ν-(ίν6烷基）胺基、Ν,Ν-Κη烷基）2胺基、Cu 烷醯胺基、N-Ch烷基）胺甲醯基、Ν，Ν-((^_6烷基）2胺甲醯 基、（V6烷基S(0)a，其中a為0至2，Ch烷氧羰基、N-(CV6 烧基）胺續酿基、N，N-(Ci - 6烧基）2胺續酿基及Cl - 6烧基項酿 基胺基；且 R19與R21係獨立選自鹵基、硝基、氰基、羥基、三氟曱 氧基、三氟甲基、胺基、羧基、胺甲醯基、巯基、胺石黃醯 基、甲基、乙基、丙基、異丙基、環丙基、環丁基、甲氧 基、乙氧基、乙醯基、乙醯氧基、甲胺基、乙胺基、二曱 胺基、二乙胺基、N-甲基-N-乙胺基、乙醯胺基、N-甲基胺 120858 200811169 甲I基、N-乙基胺甲醯基、N，N_二曱基胺甲醯基、N，N_二乙 基胺甲醯基、N-甲基乙基胺甲醯基、甲硫基、乙硫基、 甲基亞磺醯基、乙基亞磺醯基、曱烷磺醯基、乙基磺醯基、 甲氧羰基、乙氧羰基、队甲基胺磺醯基、队乙基胺磺醯基、 N，N-二甲基胺磺醯基、N，N_二乙基胺磺醯基或n_曱基·化乙 基胺磺醯基； 或其藥學上可接受之鹽或活體内可水解酯。 2_如凊求項1之式（I)化合物或其藥學上可接受之鹽或活體内 可水解酯，其中環A為一氮七圜烷基、3_氮雙環并卩丄〇] 己烷-3-基、六氫吡啶_3_基、六氫吡啶冰基、四氫吡咯_3•基 或8-氮雙環并[3.2.1]辛；基。 3·如請求項1或2中任一項之式①化合物或其藥學上可接受 之鹽或活體内可水解酯，其中Ri為氮上之取代基，且係選 自氫、c卜6烷基' c卜6烷醯基、胺甲醯基、n_(Ci-6烷基）胺 甲酿基、N，N_(Ci ·6烷基）胺甲醯基、胺磺醯基、N-CC! _6烷基） 胺磺醯基、Ν，Ν-((ν6烷基h胺磺醯基、烷氧羰基、Ci6 垸基崎醯基、Ci _ 6稀基績g藍基或雜環基_R7 ;其中r1可視情 況在碳上被一或多個R8取代；且其中若該雜環基含有-部份基團，則該氮可視情況被選自R9之基團取代； R7係選自 _C(0)_、-C(0)N(R15)·、-s(0)2-或-S〇2n(R16&gt;;其 中R15與R16為氫； R8係選自函基、石肖基、經基、胺基、q _ 6烧基、q _ 6烧 氧基、N-A - 6烷基）胺基、N，N-(Ci - 6烷基)2胺基、碳環基_Rl 7 _ 或雜環基-R18-;其中R8可視情況在碳上被一或多個RI9取 120858 200811169 代，且其中若該雜環基含有___部份基團，則該氮可視情 況被選自R20之基團取代； R9與R2G係獨立選自Ch烷基、q_6烷醯基、烷氧羰 基及芊氧羰基；其中&quot;與尺^可互相獨立地視情況在碳上 被一或多個R21取代； R與R18係獨立選自直接鍵結或-N(R22)_ ;其中R22係選 自氫或Cb6烷基；且 Rl9與R21係獨立選自鹵基、氰基、羥基、胺甲醯基、甲 基、丙基、環丙基及甲氧基。 如明求項1-3中任一項之式（I)化合物或其藥學上可接受之 鹽或活體内可水解酯，其中q為〇。 月长項1-4中任一項之式（I)化合物或其藥學上可接受之 鹽或活體内可水解酯，其中R3為鹵基。 6.如請求項1_5中任—項之式(1)化合物或其藥學上可接受之 鹽或活體内可水解酯’其中n為❹或}。 7 士0 -V 士 _靖來項丨―6中任一項之式（I)化合物或其藥學上可接受之 8鹽=活體内可水解醋，其中r4係選自異丙基或環戊基。 8.=睛求項U中任一項之式（D化合物或其藥學上可接受之 息或’舌體内可水解酯，其中R5為曱基。 9·種式（I)化合物： 120858 200811169Ring A is a 5-7 membered saturated heterocyclic ring containing a nitrogen atom and optionally 1 or 2 other heteroatoms selected from N, 〇 or s; wherein 2 atoms of the ring VIII are optionally bridged R1 is a substituent on the nitrogen and is selected from the group consisting of hydrogen, Ci 6 alkyl, Ci 6 alkyl fluorenyl, amine carbaryl, N-(C hexaalkyl)amine carbhydryl, n, n _ (Ch Alkyl)aminomethane, N-(Ci.6 alkenyl)amine,carboxylidene, anthracene, fluorene-beta-alkenyl)amine, mercaptoxyl, alkylsulfonyl, N,N_ (Ci6 alkylamine sulfonyl, N-d6 alkenyl) amine sulfonyl, N,N-(Ci-6 alkenyl) 2 amine sulfonyl, Ci 6 alkoxy group, Ch-based thiol group, (^_6 alkenyl fluorenyl, carbocyclyl-R6 or heterocyclyl-R7; wherein R1 may be optionally substituted on the carbon by one or more R8; and wherein the right hexazone contains -NH·» a group, the nitrogen may be optionally substituted by a group selected from R9; R2 is a substituent on carbon and is selected from the group consisting of a halogen group, a nitro group, a cyano group, a hydroxyl group, an amine group, a thiol group, and an amine group. Base, Wei, amine, Ci-6, C2-6 alkenyl, C2-6 alkynyl, Cb6 alkoxy, Ch alkyl sulfhydryl, q-6 alkane Oxy, N-(Ch alkyl)amino, N,N-(Ch alkyl) 2 amine, C 6 octadecylamine 120858 200811169 base, N-(Ch alkyl)amine mercapto, alkyl Alkyl fluorenyl, Cl_6 alkyl S(0)a, wherein a is 0 to 2, Cw alkoxycarbonyl, alkyl)amine sulfonyl, fluorene, fluorene-fluorene -6 alkyl h-sulfonyl Ci -6 alkylsulfonylamino, carbocyclyl-R1G- or heterocyclyl-R11-; wherein R2 may be optionally substituted on the carbon by one or more R12; and wherein if the heterocyclic group contains a group, wherein the nitrogen may be optionally substituted with a group selected from R13; q is 0-4; wherein R2 may be the same or different; R3 is selected from halo, cyano or amine; η is 0 to 2, wherein the meaning of R3 may be the same or different; R4 is selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tri-butyl, cyclopropyl, cyclo Propylmethyl, μcyclopropylethyl, cyclobutylindenyl, cyclopentyl or cyclobutyl; wherein R4 may optionally be substituted on the carbon by one or more R14; R5 is selected from methyl, ethyl , isopropyl, fluoromethyl, difluoromethyl, monofluoromethyl, methyl lactylmethyl, bad propyl Or cyclopropyl; R6 and R7 are independently selected from -C(O)-, -C(0)N(R15)-, -S(0)2- or _S〇2N(R16)-; wherein R15 is Ri6 is independently selected from hydrogen or Ci 6 alkyl; R8 and R12 are independently selected from halo, nitro, cyano, hydroxy, amine, carboxy, amine fluorenyl, fluorenyl, sulfonyl, (^ _6 alkyl, C2_6 alkenyl, 〇2_6 alkynyl, CV6 alkoxy, (: 6 alkyl alkanoyl, Ch alkyl decyloxy, N-(Ch alkyl) amine, N, N- (Ch alkyl a 2-amino group, a Ch decylamino group, an n-(Ch aryl)aminocarboxamyl group, an N,N-(Ch alkyl) 2 amine carbaryl group, a Cu alkyl group S(0)a, wherein a is 0 To 2,q-6 alkoxycarbonyl, NjCu alkyl)amine sulfonyl, ΗΝ·% _6 alkyl hamine, q-6 alkyl amide, hinder ring 120858 200811169 _R17- or Heterocyclyl-R18-; wherein hydrazine and hydrazine are independently substituted, independently of one another, by one or more R19; and wherein if the heterocyclyl contains a _cis- moiety, the nitrogen Optionally, it is substituted with a group selected from R 2 ;; r 9 , r 13 and r 2 G are independently selected from the group consisting of Ci-6 alkyl, Ch alkyl fluorenyl, sulfonium 6 alkyl sulfonyl, Cu alkoxycarbonyl, and amine fluorenyl. , n-(Ci_6 Aminomethyl hydrazino, hydrazine, hydrazine-hydrazine -6 alkyl) amine carbaryl, aryl, oxycarbonyl, benzhydryl and phenyl sulfonyl; wherein R9, Ri3 and r2 are independently of each other Replaced by one or more R21 on carbon as appropriate; Κ10,^1,! ^7 and R18 are independently selected from direct bond, 〇_, _N(R2', C(O)-, -N(R23)C(0)·, -C(0)N(R24)-,- S(0)s-, -S02N(R25)- or -N(R26)S02-; wherein R22, R23, R24, R25 and RM are independently selected from hydrogen or Ci-6 alkyl group and s is 0-2 R14 is selected from the group consisting of a halogen group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an aminomethyl group, a thiol group, an amine group, a Ci_6 alkoxy group, a C^-6 group, a Cu alkane group. Oxy, Ν-(ίν6 alkyl)amino, hydrazine, Ν-Κηalkyl) 2 amine, Cu alkanoyl, N-Ch alkyl)amine, fluorene, fluorene-((^_6) Alkyl) 2 -aminomethylindenyl, (V6 alkyl S(0)a, wherein a is 0 to 2, Ch alkoxycarbonyl, N-(CV6 alkyl)amine, N,N-(Ci - 6 alkyl) 2 amine continuation base and Cl - 6 alkyl base amine; and R19 and R21 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl , amine group, carboxyl group, amine mercapto group, mercapto group, amine phosphazenyl group, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, methoxy group, ethoxy group, ethyl fluorenyl group, Ethyloxy, methylamino, ethylamino, diammonium, diethylamino, N- --N-ethylamino, acetamido, N-methylamine 120858 200811169 methyl I, N-ethylamine, fluorenyl, N,N-didecylaminomethyl, N, N 2 Ethylamine, mercapto, N-methylethylamine, mercapto, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, decanesulfonyl, ethylsulfonate , methoxycarbonyl, ethoxycarbonyl, methamine sulfonyl, acenayl sulfonyl, N,N-dimethylamine sulfonyl, N,N-diethylamine sulfonyl or Or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 2—A compound of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrolyzable ester in vivo, wherein ring A is a heptyl heptadecyl group, a 3-azabicycloindole] hexane-3-yl group, a hexahydropyridine-3-yl group, a hexahydropyridinium group, a tetrahydropyrrole a compound of formula 1, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of claims 1 or 2, Wherein Ri is a substituent on the nitrogen and is selected from the group consisting of hydrogen, c 6 alkyl ' c 6 alkyl adenyl, amine methyl fluorenyl , n_(Ci-6 alkyl)amine methyl, N,N_(Ci.6 alkyl)amine,carboxylidene, amidoxime, N-CC!-6 alkyl) amidoxime, anthracene, anthracene -((ν6 alkylh-amine sulfonyl, alkoxycarbonyl, Ci6 fluorenyl sulfhydryl, Ci -6 6 gram gram blue or heterocyclic _R7; wherein r1 may be one or more on carbon R8 is substituted; and wherein if the heterocyclic group contains a -partyl group, the nitrogen may optionally be substituted with a group selected from R9; R7 is selected from _C(0)_, -C(0)N ( R15)·, -s(0)2- or -S〇2n (R16&gt;; wherein R15 and R16 are hydrogen; R8 is selected from a group, a Schiffki group, a thiol group, an amine group, a q -6 alkyl group, q _ 6 alkoxy, NA-6 alkyl)amino, N,N-(Ci-6 alkyl) 2 amine, carbocyclyl_Rl 7 _ or heterocyclyl-R18-; wherein R8 may be in the carbon The above is taken by one or more RI9, 120858, 200811169, and wherein if the heterocyclic group contains a ___ moiety, the nitrogen may be optionally substituted with a group selected from R20; R9 and R2G are independently selected from Ch An alkyl group, a q_6 alkyl fluorenyl group, an alkoxycarbonyl group and a fluorenyloxycarbonyl group; wherein &quot; and the ruler can be independently substituted on the carbon by one or more R21; R and R18 Independently selected from direct bond or -N(R22)_; wherein R22 is selected from hydrogen or Cb6 alkyl; and Rl9 and R21 are independently selected from halo, cyano, hydroxy, aminemethanyl, methyl, and propyl. Base, cyclopropyl and methoxy. The compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, according to any one of items 1 to 3, wherein q is hydrazine. A compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, wherein R3 is halo. 6. A compound of the formula (1), or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester, wherein n is hydrazine or}, according to any one of claims 1 to 5. A compound of the formula (I) according to any one of the formulas of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the r4 is selected from the group consisting of isopropyl or cyclopentane base. 8. The compound of any one of the formula (D) or a pharmaceutically acceptable or o-hydrolyzable ester thereof, wherein R5 is a fluorenyl group. 9. A compound of the formula (I): 120858 200811169 其中： 環A為一氮七圜烷-3-基、（1〇：，5〇：，6«)各氮雙環并[3丄0]己 烷-3-基、（R)·六氫吡啶_3·基、⑸-六氫吡啶-3-基、六氫吡啶-4-基、四氫吡咯-3-基或内向各氮雙環并[3·2·1]辛-3-基； R1為氮上之取代基，且係選自氫、甲基、丙基、異丙基、 乙烯基磺醯基、甲烷磺醯基、苄氧羰基、第三-丁氧羰基、 乙醯基、苯乙基、乙氧羰基、2-甲氧基乙基、胺磺醯基、 Ν，Ν-二甲基胺磺醯基、Ν，Ν-二甲基胺曱醯基、苄基、胺甲 醯基、Ν-甲基胺甲醯基、2-(二曱胺基）乙基磺醯基、2-(Ν-甲 基-Ν-異丙基）乙基磺醯基、2-(1-甲基六氫吡畊-4-基）乙基磺醯 基、2·四氫吡咯小基乙基磺醯基、2-(3-氟基四氫吡咯-1-基） 乙基磺醯基、2-(硫代嗎福啉-4-基）乙基磺醯基、2-(4-甲基六 氫吡啶-1-基）乙基磺醯基、2-(高六氫吡啶-1-基）乙基磺醯 基、2-二乙胺基乙基磺醯基、2-—氮四圜-1-基乙基磺醯基、 2-嗎福淋基乙基石黃酿基、2-(4-氟基六氮π比σ定-1-基）乙基石黃酿 基、2-(4-氣基六氣叶b σ定-1-基）乙基石黃酿基、2-(4-丙基六氯外匕 啶小基）乙基磺醯基、2-(4-胺曱醯基六氫吡啶-1-基）乙基磺醯 基、2-(7-氮雙環并[2·2·1]庚-7-基）乙基磺醯基、2-(2-氮雙環并 120858 -6- 200811169 P.2.2]辛-2-基）乙基磺醯基、2-(6-氮雙環并[2.2.2]辛-6-基）乙基 磺醯基、2-高嗎福啉基乙基磺醯基、2-(2-酮基六氫吡畊冰 基）乙基磺醯基、2-(1-乙醯基六氫吡畊-4-基）乙基磺醯基、2-(2-甲氧基乙胺基）乙基石黃酿基、2-(N-甲基-N-環丙基）乙基績酿 基、2-(2-酮基高六氫吡畊-4-基）乙基磺醯基、2-(1-乙醯基高 六氫吡畊-4-基）乙基磺醯基、2-(N-甲基-N-環丙基甲基）乙基 石黃醯基、2-(兩硫代嗎福琳-4-基）乙基石黃酿基、3-氣基丙基石黃 醯基、3-二甲胺基丙基磺醯基、3-二甲胺基-2,2-二甲基丙基 磺醯基、3-二乙胺基丙基磺醯基、3-(2-甲氧基乙胺基）丙基 磺醯基、3-[N-甲基-N-(2-甲氧基乙基）胺基]丙基磺醯基、3-說丙基石黃酿基、3-(1-經丙-2_基胺基）丙基石黃酿基、3-(1-甲基 六氫吡啼冰基）丙基磺醯基、3-(1-異丙基六氫吡畊-4-基）丙基 磺醯基、3-(6-氮雙環并ρ·2·2]辛-6-基）丙基磺醯基、3-(7-氮雙 環并[2·2·1]庚-7-基）丙基磺醯基、3-[1-(2-羥乙基）六氫吡畊-4-基]丙基石黃醯基、3-四氫外1：洛-1-基丙基石黃醯基、3-(1,4-二曱基 四氫吡咯-1-基）丙基磺醯基、3-嗎福啉基丙基磺醯基、3-(1-羥基丁 -2-基胺基）丙基磺醯基、3-(1-曱氧基丙-2-基胺基）丙基 磺醯基、3-(2-羥丙基胺基）丙基磺醯基、3-(1-羥基-3·曱基丁 -2-基胺基）丙基磺醯基、3-(1-羥基-2-曱基丙-2-基胺基）丙基磺醯 基、3-(六氫说唆-1-基）丙基績醯基、3_(環丙胺基）丙基確醯 基、3-(N-甲基環丙胺基）丙基石黃醯基、3-(環戊基胺基）丙 基磺醯基、3-(N-甲基·Ν_環戊基胺基）丙基磺醯基、3-(環丁基 胺基）丙基磺醯基、3-(Ν-甲基環丁基胺基）丙基磺醯基、 3_(異丙基胺基）丙基磺醯基、3-(Ν-甲基-Ν-異丙基胺基）丙基 120858 200811169 磺蕴基、3-(N-曱基善乙胺基）丙基磺醯基、3-[N-曱基-N-(2-氰基乙基）胺基]丙基石黃酿基、3-[N-乙基-Ν-(2-氰基乙基）胺基] 丙基磺醯基、3-—氮四圜小基丙基磺醯基、3_(環丙基甲胺 基）丙基磺醯基、3-(Ν-曱基-Ν-環丙基曱胺基）丙基磺醯基、 3-硝基各甲基丁基磺醯基、3_胺基_3_甲基丁基磺醯基、3_ 二甲基-3-甲基丁基績醯基、2-(六氫吡啶-3-基）乙醯基、2-(1· 第三-丁氧羰基六氫吡啶各基）乙醯基、(六氫吡啶冬基）乙 醯基、2-(1-第三-丁氧羰基六氫吡啶斗基）乙醯基、2_二甲胺 基乙醯基、3-(1-第三·丁氧羰基六氫吡畊_4_基）丙醯基、3-(1_ 第三_丁氧羰基六氫吡啶_4_基）丙醯基、3-(六氫吡啶-4-基）丙 醯基、3-(六氫吡畊-4-基）丙醯基、3-二甲胺基丙醯基、4-嗎 福啉基丁醯、4-二甲胺基丁醯基、1·第三-丁氧羰基_4_甲基 六氫吡啶-4-基羰基、4-曱基六氫吡啶-4-基羰基、：μ第三-丁 氧羰基-4-甲基六氫吡啶_4_基羰基、4-甲基高六氫吡畊小基 羰基、1-甲基六氫吡啶-3-基羰基、1-甲基四氫吡咯-2-基羰 基、3·二甲胺基四氫吡咯小基羰基、4_第三_丁氧羰基嗎福 啉-2-基羰基、嗎福啉-2-基羰基、1-甲基六氫吡啶-4-基胺甲 醯基、N-(l_乙基四氫吡咯_2_基甲基）胺甲醯基、Ν·(2-四氫吡 咯小基乙基）胺甲醯基、Ν-(2-二甲胺基乙基）胺甲醯基、N-(l-甲基六氫吡啶斗基）胺磺醯基、N-(l-異丙基六氫吡啶-4-基） 胺磺醯基、2-(二甲胺基）乙基胺磺醯基、2-(二乙胺基）乙基 胺磺醯基、2_(嗎福啉基）乙基胺磺醯基、2-(1-甲基六氫吡畊 -4-基）乙基胺石黃醯基、2-〇甲基四氫被π各-2-基）乙基胺績醯 基、3-(四虱p比洛-1-基）丙基胺石黃酿基、3-(3-氟基四氫卩比洛-1- 120858 200811169 基）丙基胺磺醯基、3-二甲胺基-2,2-二甲基丙基胺磺醯基、 3-(六氫外1：唆-1-基）丙基胺石黃醯基、N-甲基-n_(3-二甲胺基丙 基）胺磺醯基' 3-二甲胺基四氫吡咯+基磺醯基、丨_甲基六 氫叶t畊冰基績醯基、μ曱基六氫吡咬基績醯基、ι_異丙 基/、氫批°疋-4·基磺醯基及1-甲基高六氫p比_ _4·基石黃酸基； q為0 ; R3為氟基或氯基； η為0或1 ; R4係選自異丙基或環戊基； R5為甲基； 或其藥學上可接受之鹽或活體内可水解酯。 10·—種式（I)化合物：Wherein: Ring A is nitros-7-yl-3-yl, (1〇:,5〇:,6«) each nitrogen bicyclo[3丄0]hexane-3-yl, (R)·hexahydropyridine _3·yl, (5)-hexahydropyridin-3-yl, hexahydropyridin-4-yl, tetrahydropyrrole-3-yl or inwardly-specific nitrogen bicyclo[3·2·1]oct-3-yl; R1 Is a substituent on the nitrogen, and is selected from the group consisting of hydrogen, methyl, propyl, isopropyl, vinylsulfonyl, methanesulfonyl, benzyloxycarbonyl, tert-butoxycarbonyl, ethylidene, benzene Ethyl, ethoxycarbonyl, 2-methoxyethyl, sulfonyl, hydrazine, hydrazine-dimethylamine sulfonyl, hydrazine, hydrazine-dimethylamino fluorenyl, benzyl, amine formazan Base, Ν-methylamine-methyl fluorenyl, 2-(diamido)ethylsulfonyl, 2-(indolyl-methyl-indole-isopropyl)ethylsulfonyl, 2-(1- Methylhexahydropyridin-4-yl)ethylsulfonyl, 2·tetrahydropyrroleylethylsulfonyl, 2-(3-fluoro-tetrahydropyrrol-1-yl)ethylsulfonyl , 2-(thiomorpholin-4-yl)ethylsulfonyl, 2-(4-methylhexahydropyridin-1-yl)ethylsulfonyl, 2-(high hexahydropyridine-1 -yl)ethylsulfonyl, 2-diethylaminoethylsulfonyl, 2-nitrotetramine- 1-ylethylsulfonyl, 2-folfylethyl hexanyl, 2-(4-fluorohexanitropi-6 sigma-1-yl)ethyl stellate, 2-(4- Gas-based six gas leaves b σ -1--1-yl) ethyl fluorescein, 2-(4-propyl hexachloro-outeridine) ethyl sulfonyl, 2-(4-amine fluorenyl) Hydropyridin-1-yl)ethylsulfonyl, 2-(7-azabicyclo[2·2·1]hept-7-yl)ethylsulfonyl, 2-(2-azabicyclo-120858- 6- 200811169 P.2.2]oct-2-yl)ethylsulfonyl, 2-(6-azabicyclo[2.2.2]oct-6-yl)ethylsulfonyl, 2-homomorphine Ethylsulfonyl, 2-(2-ketohexahydropyrrolidyl)ethylsulfonyl, 2-(1-acetamidhexahydropyrrol-4-yl)ethylsulfonyl, 2-(2-methoxyethylamino)ethyl stellite, 2-(N-methyl-N-cyclopropyl)ethyl, 2-(2-keto-hexahydropyridinium 4-yl)ethylsulfonyl, 2-(1-ethylindolylhexahydropyridin-4-yl)ethylsulfonyl, 2-(N-methyl-N-cyclopropylmethyl Ethyl sulphate, 2-(dithiofenoflavin-4-yl)ethyl fluorescene, 3-a propyl propyl fluorenyl, 3-dimethylaminopropyl sulfonyl, 3-dimethylamine Base-2, 2 - dimethylpropylsulfonyl, 3-diethylaminopropylsulfonyl, 3-(2-methoxyethylamino)propylsulfonyl, 3-[N-methyl-N- (2-methoxyethyl)amino]propylsulfonyl, 3-propylidene, 3-(1-propan-2-ylamino)propyl fluorescene, 3-( 1-methylhexahydropyridinium) propylsulfonyl, 3-(1-isopropylhexahydropyrrolidin-4-yl)propylsulfonyl, 3-(6-azabicyclo-p-) 2·2]oct-6-yl)propylsulfonyl, 3-(7-azabicyclo[2·2·1]hept-7-yl)propylsulfonyl, 3-[1-(2 -hydroxyethyl)hexahydropyrrolidin-4-yl]propyl feldsin, 3-tetrahydro outside 1: cypin-1-ylpropyl fluorenyl, 3-(1,4-didecyltetrahydropyrrole-1- Propylsulfonyl, 3-morpholinylpropylsulfonyl, 3-(1-hydroxybutan-2-ylamino)propylsulfonyl, 3-(1-decyloxypropane- 2-ylamino)propylsulfonyl, 3-(2-hydroxypropylamino)propylsulfonyl, 3-(1-hydroxy-3-indolyl-2-ylamino)propyl Sulfonyl, 3-(1-hydroxy-2-mercaptopropan-2-ylamino)propylsulfonyl, 3-(hexahydroindol-1-yl)propyl, 3_(ring Apropylamino)propyl decyl, 3-(N-methyl ring Amino) propyl sulphate, 3-(cyclopentylamino)propylsulfonyl, 3-(N-methyl-indole-cyclopentylamino)propylsulfonyl, 3-(cyclobutyl Amino)propylsulfonyl, 3-(indolyl-methylcyclobutylamino)propylsulfonyl, 3-(isopropylamino)propylsulfonyl, 3-(indolyl-methyl- Ν-isopropylamino)propyl 120858 200811169 sulfonate, 3-(N-fluorenylethylidene)propylsulfonyl, 3-[N-fluorenyl-N-(2-cyanoethyl) Amino]propyl propyl sulphate, 3-[N-ethyl-indole-(2-cyanoethyl)amino]propylsulfonyl, 3-nitrotetramethylene sulfonate , 3_(cyclopropylmethylamino)propylsulfonyl, 3-(fluorenyl-fluorenyl-fluorenyl-cyclopropylguanidino)propylsulfonyl, 3-nitromethylbutylsulfonate Indenyl, 3-amino-10-methylbutylsulfonyl, 3-dimethyl-3-methylbutylmethyl, 2-(hexahydropyridin-3-yl)ethenyl, 2-(1 · Third-butoxycarbonylhexahydropyridinyl)ethinyl, (hexahydropyridinyl)ethenyl, 2-(1-tris-butoxycarbonylhexahydropyridyl)ethenyl, 2 _Dimethylaminoethyl fluorenyl, 3-(1-tert-butoxycarbonylhexahydropyrazine_4_yl)propanoid , 3-(1_3rd-butoxycarbonylhexahydropyridyl-4-yl)propanyl, 3-(hexahydropyridin-4-yl)propanyl, 3-(hexahydropyrrolidin-4-yl) Propionyl, 3-dimethylaminopropynyl, 4-morpholinylbutanyl, 4-dimethylaminobutanyl, 1·tris-butoxycarbonyl-4-methylsulfonate-4- Alkylcarbonyl, 4-mercaptohexahydropyridin-4-ylcarbonyl, :μ3 -butoxycarbonyl-4-methylhexahydropyridine-4-ylcarbonyl, 4-methylhexahydropyridinylcarbonyl , 1-methylhexahydropyridin-3-ylcarbonyl, 1-methyltetrahydropyrrole-2-ylcarbonyl, 3-dimethylaminotetrahydropyrroleylcarbonyl, 4_t-butoxycarbonyl-based Phenyl-2-ylcarbonyl, morpholin-2-ylcarbonyl, 1-methylhexahydropyridin-4-ylaminecarbamyl, N-(l-ethyltetrahydropyrrole-2-ylmethyl)amine Mercapto, Ν·(2-tetrahydropyrroleylethyl)amine, mercapto, Ν-(2-dimethylaminoethyl)amine, mercapto, N-(l-methylhexahydropyridine Aminesulfonyl, N-(l-isopropylhexahydropyridin-4-yl)aminesulfonyl, 2-(dimethylamino)ethylaminesulfonyl, 2-(diethylamino) Ethylamine sulfonyl, 2-(norpoline)ethylamine sulfonyl, 2-(1-A) Ethyl hexahydropyroxy-4-yl)ethylamine sulphate, 2-indolylmethyltetrahydro π-yl-2-yl)ethyl amide, 3-(tetraindole p-l-yl-1-yl) Propylamine yellow wine, 3-(3-fluorotetrahydropyridinium-1-120858 200811169) propylamine sulfonyl, 3-dimethylamino-2,2-dimethylpropane Amidoxime, 3-(hexahydroexo-1:indol-1-yl)propylamine fluorenyl, N-methyl-n-(3-dimethylaminopropyl)amine sulfonyl ' 3- Methylaminotetrahydropyrrole+ylsulfonyl, 丨-methylhexahydrophyllin t cultivating ice base, thiol hexahydropyridyl thiol, ι_isopropyl/hydrogen batch °疋-4· sulfonyl sulfhydryl and 1-methylhexahydrogen p ratio _ _4· fluorescens; q is 0; R 3 is fluoro or chloro; η is 0 or 1; R 4 is selected from isopropyl Or cyclopentyl; R5 is methyl; or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof. 10·-type compound of formula (I): 其係選自： 5-氣基-4-(2-甲基-3-丙-2-基-口米唾-4-基）-N-(l-曱基石黃酿基-4- 六氫峨唆基）嘧咬-2-胺； 5-氣基_4-(2-甲基-3-丙-2-基-味嗤-4-基）_Ν-[1-(2-四氮？比哈-I-基乙基磺醯基）-4-六氫吡啶基]喊啶-2-胺； N-[l-(3•二甲胺基-3-甲基-丁基）續醯基-4-六氫吡啶基]-5-氟 基-4-(2-甲基-3-丙-2_基-口米唾-4-基）口密。定-2-胺； 120858 -9 - 200811169 N-[ 1-(3-氣基丙基石黃醯基）冰六氫p比σ定基]說冰(2_甲基-3-丙_2-基-味峻冬基户密咬-2-胺； 5-氟基-4_(2-甲基-3-丙_2_基-。米°坐-4_基）·Ν_[1-(3-四氫峨洛-1-基丙基石黃龜基Μ-六氫咐σ定基]痛σ定胺； 5-氟基-4_(2-甲基-3-丙-2-基-咪唑-4-基）-N-[l-[3-(l-六氫吡啶 基）丙基磺醯基]-4-六氫吡啶基]嘧啶-2-胺； Ν-[1-[2-(6-氮雙環并[2·2·2]辛-6-基）乙基磺醯基]-4-六氫吡啶 基]-5-iL基-4-(2-甲基-3-丙_2_基-口米°坐-4-基）嘴σ定-2-胺； Ν-[Η3-(6-氮雙環并[2.2.2]辛-6-基）丙基磺醯基]冬六氫吡啶 基]-5_氣基-4-(2-曱基-3-丙_2_基-味〇坐-4-基）口密σ定_2_胺； Ν-[Η3-(7-氮雙環并_7_基）丙基磺醯基]冬六氫吡啶 基]_5-氟基冰(2-甲基-3-丙-2-基-味唑冰基）,密唆_2·胺；及 5_氟基冰(2-甲基-3-丙-2-基』米唑-4-基）-N-[l-[(l-丙-2·基-4-六 氫吨唆基）續醯基]冰六氫吡啶基]嘧啶冬胺； 或其藥學上可接受之鹽或活體内可水解酯。 活體内可水解酯之方法 團均如請求項丨中之定 才法4使式（II)嘧啶： 種氣備如明求項1之式①化合物或其藥學上可接受鹽或 -方法，其中除非另有指明，否則可變基 之定義，該方法係包括：It is selected from the group consisting of: 5-Alkyl-4-(2-methyl-3-propan-2-yl-mole-4-indolyl-4-yl)-N-(l-fluorenyl sulphate-4-hexahydro Mercapto) pyridin-2-amine; 5-carbyl_4-(2-methyl-3-propan-2-yl-miso-4-yl)_Ν-[1-(2-tetrazine? Biha-I-ylethylsulfonyl)-4-hexahydropyridinyl]oxidine-2-amine; N-[l-(3•dimethylamino-3-methyl-butyl) 醯The base 4-hexahydropyridyl]-5-fluoro-4-(2-methyl-3-propan-2-yl-m-propan-4-yl) is densely packed. -2--2-amine; 120858 -9 - 200811169 N-[ 1-(3-Alkylpropyl sulphate) ice hexahydro-p ratio σ determinate] said ice (2_methyl-3-propan-2-yl-flavor冬冬基家密 bit-2-amine; 5-fluoro-4-(2-methyl-3-propan-2-yl-.m.--4-yl)·Ν_[1-(3-tetrahydro)峨洛-1-ylpropyl stone yellow turtle Μ 六 hexahydro 咐 定 ] ] ] ] ] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -N-[l-[3-(l-hexahydropyridyl)propylsulfonyl]-4-hexahydropyridinyl]pyrimidin-2-amine; Ν-[1-[2-(6-nitrobicyclo) And [2·2·2]oct-6-yl)ethylsulfonyl]-4-hexahydropyridinyl]-5-iL-yl-4-(2-methyl-3-propan-2-yl- Mouth °-4-yl) Mouth sigma-2-amine; Ν-[Η3-(6-azabicyclo[2.2.2]oct-6-yl)propylsulfonyl] winter hexahydropyridyl ]-5_ gas-based 4-(2-mercapto-3-propan-2-yl-miso-4-yl)-densified sigma-2-amine; Ν-[Η3-(7-nitrobicyclo) And _7_yl) propylsulfonyl] winter hexahydropyridyl]_5-fluoro-based ice (2-methyl-3-propan-2-yl-isoxazole ice-based), hydrazine-2. amine; And 5-_fluoro-based ice (2-methyl-3-propan-2-yl) carbazol-4-yl)-N-[l-[(l-propan-2-yl-4-hexahydro fluorenyl) Rhodium hexahydropyridyl pyrimidine Or a pharmaceutically acceptable salt thereof or a hydrolyzable ester in vivo. The method of hydrolyzing an ester in vivo is as defined in the claim 4, and the pyrimidine of the formula (II) is prepared as follows: A compound of formula 1 or a pharmaceutically acceptable salt or method thereof, wherein unless otherwise indicated, the definition of a variable group, the method comprising: 120858 -10- 200811169 其中L為可置換基團；與式（III)胺反應：120858 -10- 200811169 wherein L is a replaceable group; reacts with an amine of formula (III): 或 才法W使式（IV)化合物：Or the compound of formula (IV): 與式（V)化合物反應： RxReaction with a compound of formula (V): Rx 6烧基 其中T為Ο或S; Rx可為相同或不同，且係選自（ 或 才法Θ使式（VI)嘧啶：6 alkyl group wherein T is hydrazine or S; Rx may be the same or different, and is selected from (or grammatically: pyrimidine of formula (VI): 120858 -11 - 200811169120858 -11 - 200811169 (VII) 與式（VII)化合物反應 其中Y為可置換基團； 及接著若必要，則： i) 使式（I)化合物轉化成另一種式（I)化合物； ϋ)移除任何保護基； 形成藥學上可接受之鹽或活體内可水解酯。 12. —種醫藥組合物，其包含如請求項m中任一項之式⑴化 合物或其藥學上可接受之鹽或活體内可水解g旨，與藥學上 可接受之稀釋劑或載劑。 13·如請求項M〇中任一項之式①化合物或其藥學上可接受 之鹽或活體内可水解酯，其係作為藥劑使用。 1屯一種如請求項M0中任一項之式（1)化合物或其藥學上可 接又之鹽或活體内可水解酯於藥劑製造上之用途，該藥劑 係用於產生抗細胞增生作用。 15· —種如請求項 1中 — ^ 、 、之式（I)化合物或其藥學上可 接义之鹽或活體内可水解ss於姑 〆 餸円』水解§曰於樂劑製造上之用途，該藥劑 係用於產生CDK2抑制作用。 16· —種如請求項中 項之式（I)化合物或其藥學上可 接又之皿或、居體内可水解酷 展田认 篮円J R解酉日於樂劑製造上之用途，該藥劑 係用於治療癌症。 17. —種如請求項丨_1〇 貝 &lt; 式（I)化合物或其藥學上可 120858 -12- 200811169 接受之鹽或活體内可水解酯於藥劑製造上之用途，該藥劑 係用於治療白血病或淋巴樣惡性病症，或***、肺臟、結 腸、直腸、胃、肝臟、腎臟、***、膀胱、胰臟、女陰、 皮膚或卵巢之癌症。 •種如睛求項M0中任一項之式（I)化合物或其藥學上可 接受之鹽或活體内可水解醋於藥劑製造上之用途，該藥劑 ::::治療癌症、纖維增生與分化病症、牛皮癬、風濕: :人卡波西氏肉瘤、血管瘤、急性與慢性腎病、動脈 與二=T、動脈再狹窄、1身免疫疾病、急性 病。 m扃及伴隨著視賴血管增生之眼部疾 !20858 200811169 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：(VII) reacting with a compound of formula (VII) wherein Y is a displaceable group; and if necessary: i) converting a compound of formula (I) to another compound of formula (I); ϋ) removing any protecting groups Forming a pharmaceutically acceptable salt or an in vivo hydrolysable ester. 12. A pharmaceutical composition comprising a compound of formula (1) according to any one of claims m, or a pharmaceutically acceptable salt thereof or a hydrolyzable in vivo, and a pharmaceutically acceptable diluent or carrier. 13. A compound of formula 1 according to any one of claims M, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a medicament. A use of a compound of the formula (1) according to any one of claims M0, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, for the manufacture of a medicament for producing an anti-cell proliferative effect. 15. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a hydrolyzable ss in vivo, in the manufacture of the agent This agent is used to produce CDK2 inhibition. 16. The use of a compound of the formula (I) as claimed in the claims or a pharmaceutically acceptable dish thereof, or a hydrolyzable cool field identification basket in the body, the use of the JR solution for the manufacture of the agent, The system is used to treat cancer. 17. The use of a compound of formula (I), or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for the manufacture of a medicament, as claimed in the claims 丨_1 〇 & & 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 858 Treatment of leukemia or lymphoid malignancy, or cancer of the breast, lung, colon, rectum, stomach, liver, kidney, prostate, bladder, pancreas, genital, skin or ovary. The use of a compound of the formula (I) according to any one of the items M0, or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable vinegar, for the manufacture of a medicament:::: for treating cancer, fibrosis and Differentiation disorders, psoriasis, rheumatism:: Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, arterial and secondary = T, arterial restenosis, 1 body immune disease, acute disease. m扃 and eye diseases accompanied by vascular hyperplasia! 20858 200811169 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: When there is a chemical formula, please reveal the chemical formula that best shows the characteristics of the invention: 120858120858
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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8178529B2 (en) 2009-04-15 2012-05-15 Astrazeneca Ab Imidazole substituted pyrimidines
JP5667913B2 (en) * 2011-03-15 2015-02-12 住友化学株式会社 Method for producing 2,3-dichloropyridine
EP2836482B1 (en) * 2012-04-10 2019-12-25 The Regents of The University of California Compositions and methods for treating cancer
CN107987054B (en) * 2017-11-28 2020-05-19 四川大学 CDK2 inhibitor
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
TW202100520A (en) 2019-03-05 2021-01-01 美商英塞特公司 Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
JP2023509260A (en) * 2019-08-14 2023-03-08 インサイト・コーポレイション Imidazolylpyrimidinylamine compounds as CDK2 inhibitors
WO2021072232A1 (en) 2019-10-11 2021-04-15 Incyte Corporation Bicyclic amines as cdk2 inhibitors

Family Cites Families (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4659363A (en) * 1983-07-25 1987-04-21 Ciba-Geigy Corporation N-(2-nitrophenyl)-2-aminopyrimidine derivatives, the preparation and use thereof
US4983608A (en) * 1989-09-05 1991-01-08 Hoechst-Roussell Pharmaceuticals, Inc. N-substituted-4-pyrimidinamines and pyrimidinediamines
US5521184A (en) * 1992-04-03 1996-05-28 Ciba-Geigy Corporation Pyrimidine derivatives and processes for the preparation thereof
US5516775A (en) * 1992-08-31 1996-05-14 Ciba-Geigy Corporation Further use of pyrimidine derivatives
EP0664291B1 (en) * 1992-10-05 2000-07-19 Ube Industries, Ltd. Pyrimidine compound
US5739143A (en) * 1995-06-07 1998-04-14 Smithkline Beecham Corporation Imidazole compounds and compositions
ES2239357T3 (en) * 1996-06-10 2005-09-16 MERCK &amp; CO., INC. REPLACED IMIDAZOLS THAT HAVE INHIBITING ACTIVITY OF CYTOKINS.
EP1054004B1 (en) * 1997-12-15 2008-07-16 Astellas Pharma Inc. Novel pyrimidine-5-carboxamide derivatives
US6200977B1 (en) * 1998-02-17 2001-03-13 Tularik Inc. Pyrimidine derivatives
AU5438499A (en) * 1998-08-29 2000-03-21 Astrazeneca Ab Pyrimidine compounds
ES2274634T3 (en) * 1998-08-29 2007-05-16 Astrazeneca Ab PIRIMIDINE COMPOUNDS.
GB9905075D0 (en) * 1999-03-06 1999-04-28 Zeneca Ltd Chemical compounds
GB9907658D0 (en) * 1999-04-06 1999-05-26 Zeneca Ltd Chemical compounds
GB9919778D0 (en) * 1999-08-21 1999-10-27 Zeneca Ltd Chemical compounds
US7101869B2 (en) * 1999-11-30 2006-09-05 Pfizer Inc. 2,4-diaminopyrimidine compounds useful as immunosuppressants
GB0004886D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004888D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004890D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0004887D0 (en) * 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
GB0007371D0 (en) * 2000-03-28 2000-05-17 Astrazeneca Uk Ltd Chemical compounds
GB0016877D0 (en) * 2000-07-11 2000-08-30 Astrazeneca Ab Chemical compounds
GB0021747D0 (en) * 2000-09-04 2000-10-18 Cambridge Consultants Coating removal
GB0021726D0 (en) * 2000-09-05 2000-10-18 Astrazeneca Ab Chemical compounds
GB0103926D0 (en) * 2001-02-17 2001-04-04 Astrazeneca Ab Chemical compounds
CA2435177A1 (en) * 2001-02-20 2002-08-29 Astrazeneca Ab 2-arylamino-pyrimidines for the treatment of gsk3-related disorders
SE0100569D0 (en) * 2001-02-20 2001-02-20 Astrazeneca Ab New compounds
MXPA03010810A (en) * 2001-05-29 2004-03-22 Schering Ag Cdk inhibiting pyrimidines, production thereof and their use as medicaments.
GB0113041D0 (en) * 2001-05-30 2001-07-18 Astrazeneca Ab Chemical compounds
EP1444223A1 (en) * 2001-11-07 2004-08-11 F. Hoffmann-La Roche Ag Aminopyrimidines and -pyridines
JP2005524672A (en) * 2002-03-09 2005-08-18 アストラゼネカ アクチボラグ Imidazolyl-substituted pyrimidine derivatives having CDK inhibitory activity
GB0205690D0 (en) * 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
GB0205693D0 (en) * 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
GB0205688D0 (en) * 2002-03-09 2002-04-24 Astrazeneca Ab Chemical compounds
GB0311276D0 (en) * 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
GB0311274D0 (en) * 2003-05-16 2003-06-18 Astrazeneca Ab Chemical compounds
TW200528101A (en) * 2004-02-03 2005-09-01 Astrazeneca Ab Chemical compounds
WO2006034872A1 (en) * 2004-09-29 2006-04-06 Bayer Schering Pharma Aktiengesellschaft Substituted 2-anilinopyrimidines as cell cycle kinase inhibitors or receptor tyrosine kinase inhibitors, production of said substances and use of the latter as medicaments
RU2007114080A (en) * 2004-10-13 2008-11-27 Вайет (Us) N-BENZylSULPHONIL-SUBSTITUTED ANALOGUES OF ANILINOPYRIMIDINE
EP1828183A1 (en) * 2004-12-17 2007-09-05 AstraZeneca AB 4- (4- (imidazol-4-yl) pyrimidin-2-ylamino) benzamides as cdk inhibitors
GB0504753D0 (en) * 2005-03-08 2005-04-13 Astrazeneca Ab Chemical compounds
EP2301928A1 (en) * 2005-07-30 2011-03-30 AstraZeneca AB Imidazolyl-pyrimidine compounds for use in the treatment of proliferative disorders
CA2623374A1 (en) * 2005-09-30 2007-04-05 Astrazeneca Ab Imidazo [1,2-a] pyridine having anti-cell-proliferation activity
AR058073A1 (en) * 2005-10-03 2008-01-23 Astrazeneca Ab IMIDAZOL 5-IL-PYRIMIDINE DERIVATIVES, OBTAINING PROCESSES, PHARMACEUTICAL COMPOSITIONS AND USES
US20080214560A1 (en) * 2005-10-03 2008-09-04 Astrazeneca Ab Use of Pyrimidine Derivatives in the Manufacture of a Medicament for Prevention and/or Treatment of Alzheimer's Disease
WO2007138277A1 (en) * 2006-05-26 2007-12-06 Astrazeneca Ab 2-carbocycloamino-4-imidaz0lylpyrimidines as agents for the inhbition of cell proliferation
TW200815418A (en) * 2006-06-27 2008-04-01 Astrazeneca Ab New compounds I
TW200815417A (en) * 2006-06-27 2008-04-01 Astrazeneca Ab New compounds II

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